Journal of Biochemical and Molecular Toxicology

Cystathionine‐γ‐Lyase/Hydrogen Sulfide Axis Plays a Crucial Role in Promoting the Progression of Cervical Cancer

ABSTRACT The role of endogenous hydrogen sulfide (H 2 S) in the pathophysiological mechanisms of various organ tumors has been extensively studied; however, its relevance to cervical cancer remains unexplored. This study aimed to examine the effect of endogenous H 2 S and its main synthetic enzyme, cystathionine‐γ‐lyase (CSE), in regulating the growth behavior in cervical cancer cells. The proliferation, migration, and invasion of C33A and HeLa cervical cancer cells were investigated, followed by molecular, biochemical, and immunocytochemical analyses. The results indicated that CSE is highly expressed in C33A and HeLa cells and modulates the levels of endogenous H 2 S. CSE knockdown suppressed the proliferation, migration, and invasion of cervical cancer cells. The CSE‐mediated growth patterns involved epithelial–mesenchymal transition (EMT), mitochondrial apoptosis, pyroptosis, reactive oxygen species (ROS) production, and the PI3K/AKT/mTOR signaling pathway. Additionally, CSE knockdown inhibited the growth of xenograft tumors in vivo. Similarly, CSE overexpression was performed for reverse verification. In brief, inhibition of CSE reduced cervical cancer growth, while overexpression of CSE promoted it. These findings indicated that CSE may serve as a potential target for early diagnosis, prognosis assessment, and therapeutic intervention in cervical cancer.

Effects of silencing hsa_circ_0015326 on proliferation, migration, invasion, and apoptosis of epithelial ovarian cancer cells

AbstractAlthough the treatment of ovarian cancer has made great progress, there are still many patients who are not timely detected and given targeted therapy due to unknown pathogenesis. Recent studies have found that hsa_circ_0015326 is upregulated in ovarian cancer and is involved in the proliferation, invasion, and migration of ovarian cancer cells. However, whether hsa_circ_0015326 can be used as a new target of ovarian cancer needs further investigation. Therefore, the effect of hsa_circ_0015326 on epithelial ovarian cancer was investigated in this study. At first, si‐hsa_circ_0015326 lentivirus was transfected into epithelial ovarian cancer cells. Then real‐time fluorescence quantitative PCR (qRT‐PCR) was used to detect hsa_circ_0015326 level. The proliferation of ovarian cancer cells was detected by CCK‐8 assay. The horizontal and vertical migration abilities of the cells were detected by wound‐healing assay and Transwell assay, respectively. Transwell assay was also used to determine the invasion rate. As for the apoptosis rate, it was assessed by flow cytometry. As a result, the expression level of hsa_circ_0015326 in A2780 and SKOV3 was found to be higher than that in IOSE‐80. However, after transfecting si‐hsa_circ_0015326 and si‐NC into the cells, the proliferation, migration, and invasion abilities of A2780 and SKOV3 cells in the si‐hsa_circ_0015326 group were significantly reduced in comparison to those in the si‐NC and mock groups, while their apoptosis rates were elevated. Collectively, silencing hsa_circ_0015326 bears the capability of inhibiting the proliferation, migration, and invasion of ovarian cancer cells while increasing apoptosis rate. It can be concluded that hsa_circ_0015326 promotes the malignant biological activities of epithelial ovarian cancer cells.

MicroRNA‐505‐3p mediates cell motility of epithelial ovarian cancer via suppressing PEAK1 expression

Abstract MicroRNAs (miRNAs) are a class of small RNA genes with important roles in cancer biology regulation. There are considerable studies regarding the roles of microRNA‐505‐3p (miR‐505‐3p) in cancer development and progression, but the function of miR‐505‐3p in epithelial ovarian cancer (EOC) has not been fully clarified. Comparative analysis of miRNA expression data set was used to select differentially expressed miRNAs. Quantitative real‐time polymerase chain reaction was applied to detect expression levels of RNAs, while western blot and immunofluorescence staining were performed to detect expression levels of proteins of interest. The motility of EOC cells was assessed by wound healing and transwell assays. The binding and regulating relationship between miRNA and its direct target gene was investigated by dual‐luciferase assay. Our results show that miR‐505‐3p was upregulated in recurrent EOC, which significantly inhibits EOC cell motility via modulating cell epithelial–mesenchymal transition. Furthermore, our results indicated that PEAK1 expression was inhibited by direct binding of miR‐505‐3p into its 3′‐URT in EOC cells. Importantly, knockdown of PEAK1 attenuated the effect of mi‐505‐3p inhibitor on EOC cell migration and invasion. In conclusion, our findings indicate that miRNA‐505‐3p inhibits EOC cell motility by targeting PEAK1.

Synthesis, characterization, and biological properties of novel Schiff bases containing pentafluorophenyl hydrazine

AbstractIn the present study, new Schiff bases derived from pentafluorophenyl‐hydrazine (L1, L2, L3, L4) were synthesized and their structures were characterized by 1H nuclear magnetic resonance spectroscopy (NMR), 13C NMR, 19F NMR, fourier transform infrared spectroscopy, and elemental analysis methods. Then, the anticancer activities of the obtained compounds were investigated using three human cancer cell lines (A2780, over; Caco‐2, colon; and HT‐29 colon carcinoma cell lines). According to the obtained cytotoxicity results, compound number L4 was found to have the highest anticancer activity in A2780 (over) and Caco‐2 (colon) cell lines. Furthermore, in silico, ADMET properties, where studies play an important role in the development and prediction of drug compounds, were calculated using web‐based platforms. In addition, molecular docking studies were performed to evaluate the binding interactions between the synthesized pentafluorophenyl‐hydrazone compounds and the MDM2 protein (4JSC). Both in vitro and in silico results showed that the synthesized compounds could act as potent anticancer agents.

Long noncoding RNA DARS‐AS1 regulates TP53 ubiquitination and affects ovarian cancer progression by modulation miR‐194‐5p/RBX1 axis

AbstractBackgroundOvarian cancer is a malignant tumor with a poor prognosis, its underlying mechanism is still unclear.ObjectiveIn this study, long noncoding RNA DARS‐AS1 was studied to identify its function in the development of ovarian cancer.MethodsPerform functional experiments to detect the effects of DARS‐AS1 on the proliferation, apoptosis, and migration of ovarian cancer cells A2780. The luciferase report, immunoprecipitation (IP) experiment, and ubiquitination level determination verify that RBX1 ubiquitination and mediate the degradation of tumor suppressor gene TP53.ResultsKnockdown of DARS‐AS1 can inhibit cell proliferation, migration, and apoptosis, and the application of miR‐194‐5p inhibitors can prevent this process. Luciferase and IP experiments showed that DARS‐AS1 regulates the expression of RBX1 by binding to miR‐194‐5p, and RBX1 mediates its degradation through ubiquitination of TP53.

Polypeptide LTX‐315 reverses the cisplatin chemoresistance of ovarian cancer cells via regulating Beclin‐1/PI3K/mTOR signaling pathway

AbstractObjectivePolypeptide LTX‐315 induces immunogenic cell death, thus having the potential to improve the effect of anticancer treatment. However, the function of LTX‐315 in reversing chemoresistance in ovarian cancer (OC) still remains elusive. Our study aims to decipher the effect of LTX‐315 on reversing the chemoresistance of OC cells and explore its mechanism.MethodsSKOV3, A2780, SKOV3/DDP, and A2780/DDP cells (cisplatin [DDP]‐resistant cells] were treated with different concentrations of LTX‐315 (10 and 20 µmol/L), respectively. Cell counting kit‐8 assay, Transwell assay, and flow cytometry were used to assess cell viability, migration, invasion, apoptosis rate, and cell cycle of the cells. Western blot was performed to examine the expression of cleaved caspase 3, caspase 3, cleaved Poly (ADP‐ribose) polymerase (PARP), PARP, Bax, Bcl‐2, Beclin‐1, p‐Akt, Akt, p‐mammalian target of rapamycin (mTOR), and mTOR. Furthermore, OC cells were treated with autophagy inhibitor 3‐methyladenine (3‐MA), and “rescue experiments” were performed.ResultsDDP‐resistant OC cell models were established, and LTX‐315 treatment resulted in lower IC50 of DDP. In OC cells treated with LTX‐315, the viability, migration, invasion and the expression of Bcl‐2 of were repressed, but the apoptotic rate and the expression of cleaved caspase 3, cleaved PARP and Bax were increased, and the cell cycle was arrested. Moreover, LTX‐315 promoted Beclin‐1 expression level and inhibited p‐Akt and p‐mTOR expression levels, whereas 3‐MA could partially reverse the biological effects of LTX‐315 on OC cells.ConclusionLTX‐315 can inhibit the resistance of OC cells to DDP in vitro and plays a role by regulating Beclin‐1/phosphatidylinositol‐3‐kinase/mTOR signaling pathway.

Syringic acid regulates suppression of the STAT3/JNK/AKT pathway via inhibition of human ovarian teratoma cancer cell (PA‐1) growth—in vitro study

AbstractAmong the various gynaecological cancers, ovarian cancer (OC) is the third most severe cancer worldwide affecting women. Syringic acid (SRA) exhibits several hypoglycaemia, antioxidant, and anti‐inflammatory properties. The study aimed to examine the proapoptotic activities of SRA on OC in PA‐1 cells. SRA has been shown to decrease cell viability, increase the rate of cell apoptosis, and cause mitochondrial membrane potential to dissipate and induce over‐accumulation of intracellular reactive oxygen species in PA‐1 cells after 24 h of exposure. We examined the anticancer efficacy of SRA with its responsible molecular mechanism in the PA‐1 cell lines of human OC. In a dose‐dependent manner, SRA substantially suppressed cell proliferation and migration. SRA exhibited significant downregulation of cyclins including CDK2, CDK4, and Cyclin D1 responsible for cell‐cycle regulation. The apoptosis‐mediated anticancer activity was mainly mediated through caspase‐3, caspase‐8, caspase‐9 and Bax upregulation, and Bcl‐2 downregulation. We report that SRA significantly inhibits the expression of signal transducer and activator of transcription 3 (STAT3), c‐Jun N‐terminal kinase (JNK), P65, and protein kinase B (AKT) pathways. These findings depict the effective inhibition of STAT3, p38, and AKT expression by SRA, making it a potential therapeutic candidate for human OC.

Hsa_circ_0000119 promoted ovarian cancer development via enhancing the methylation of CDH13 by sponging miR‐142‐5p

AbstractOvarian cancer is the leading cause of gynecological cancer‐related death in women, and is difficult to treat. The aim of our study is to explore the role and action mechanism of hsa_circ_0000119 in ovarian cancer, thus to analyze whether the circular RNA is a potential target for the treatment of the disease. In this present study, our data shows that hsa_circ_0000119 and DNA methyltransferase 1 (DNMT1) was increased, while miR‐142‐5p was decreased in ovarian cancer. Overexpression of hsa_circ_0000119 promoted tumor growth, while silencing of hsa_circ_0000119 resulted in an opposite effects. Decreasing of hsa_circ_0000119 also notably inhibited the proliferation, migration, and invasion of the ovarian cancer cells. Moreover, the data proves that hsa_circ_0000119 negatively regulated miR‐142‐5p and cadherin 13 (CDH13) expression, but positively regulated DNMT1 expression. miR‐142‐5p could interact with hsa_circ_0000119 and DNMT1 3′‐UTR. Silencing of DNMT1 could reverse the inhibition of hsa_circ_0000119 to miR‐142‐5p and CDH13 expression. Importantly, higher level of CDH13 promoter methylation existed in the ovarian tumors than that in matched normal tissues. DNA methyltransferase inhibitor could increase the expression of CDH13 in ovarian cancer cells. In addition, our results also prove that increasing of CDH13 or miR‐142‐5p effectively reversed the inhibition of hsa _circ_0000119 to the cell malignant phenotypes. Overall, our data demonstrate that hsa_circ_0000119 facilitated ovarian cancer development through increasing CDH13 expression via promoting DNMT1 expression by sponging miR‐142‐5p. Our data demonstrate the potential role of hsa_circ_0000119 in the treatment of ovarian cancer.

The transcription factor ZEB1 mediates the progression of epithelial ovarian cancer by promoting the transcription of CircANKRD17

AbstractZinc finger E‐box‐binding homeobox 1 (ZEB1) is a key transcription factor that regulates the process of epithelial‐mesenchymal transition (EMT) in various tumors. However, its role in epithelial ovarian cancer (EOC) is far from understood. The present study aimed to explore the role and potential mechanism of action of ZEB1 in EOC. A quantitative reverse transcription‐polymerase chain reaction was used to detect ZEB1 expression levels. The Cell Counting Kit‐8 assay, transwell assays, and flow cytometry were used to verify the effects of ZEB1 on the proliferation, invasion, migration, apoptosis, and EMT of EOC, respectively. RNA sequencing identified the effect of knocking down ZEB1 on circular RNAs in EOC cells. Dual‐luciferase activity assay and chromatin immunoprecipitation experiments were used to verify the regulatory effect of ZEB1 on the circular RNA ANKRD17 (CircANKRD17; ID: hsa_circ_0007883) at the transcriptional level. Higher ZEB1 expression was found in EOC tissues and cells and was closely related to tumor metastasis, advanced stages, and lower survival rates. Furthermore, silencing ZEB1 inhibited the proliferation, invasion, migration, and EMT of EOC cells but enhanced cell apoptosis. Mechanistically, knockdown of ZEB1 resulted in the greatest downregulation of CircANKRD17 in EOC cells, and ZEB1 significantly promoted the expression of CircANKRD17 and had no significant effect on ANKRD17 messenger RNA expression. Further experiments verified that ZEB1 mediates the regulation of EOC processes by CircANKRD17. Highly expressed ZEB1 promoted proliferation, invasion, migration, and EMT while it inhibited cell apoptosis in EOC by promoting the transcription of CircANKRD17, providing a potential target for the treatment of EOC.

Shifting of cell cycle arrest from the S‐phase to G2/M phase and downregulation of EGFR expression by phytochemical combinations in HeLa cervical cancer cells

AbstractCervical cancer is a major human papillomavirus‐related disease and is the fourth leading cause of death by cancer among women. Plants are an important source of anticancer compounds and many of them are currently used in the treatment of cancer. Several reports suggest the efficacy of plant‐derived compounds increases when used in combination. This study was carried out to evaluate the effect of four plant‐derived compounds such as curcumin (C), ellagic acid (E), quercetin (Q), and resveratrol (R) when used alone or in combinations using HeLa cervical cancer cells. All four phytocompounds showed effective cytotoxic activities in targeting HeLa cervical cancer cells as determined by the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium assay. The selected phytocompound combinations C + E, C + Q, and Q + R work synergistically while the combination C + R shows additive effects. All four phytocompounds reduce cell migration as determined by in vitro wound‐healing assay. The expression level of the epidermal growth factor receptor is significantly downregulated both in individual and combination. The flow cytometry analysis of cell cycle indicates that individual drugs curcumin, ellagic acid, quercetin, and resveratrol, each with 20 µM effectively arrested cell cycle at the S‐phase while the combination of drugs (10 + 10 µM) at the G2/M phase.

Upregulation of lncRNA DARS‐AS1 accelerates tumor malignancy in cervical cancer by activating cGMP‐PKG pathway

AbstractThis paper investigates the function of lncRNA DARS‐AS1 in cervical cancer (CC) as well as its in‐depth mechanism. The differential expression of DARS‐AS1 and ATP1B2 were analyzed based on The Cancer Genome Atlas and the Genotype‐Tissue Expression databases, and the survival rate was measured using Kaplan–Meier survival analysis. Biological function experiments were performed to detect cell proliferation, invasion, and migration. Quantitative real‐time polymerase chain reaction was carried out to detect the expression of DARS‐AS1 and ATP1B2. Western blot analysis was utilized to assess the protein levels of ATP1B2 and cGMP‐PKG pathway‐related proteins. DARS‐AS1 was expressed at high levels in CC tissues and cell lines, and high expression of DARS‐AS1 indicated a lower survival rate. CCK‐8 and colony formation assays revealed that the overexpression of DARS‐AS1 promoted the proliferation of CC cells. Furthermore, bioinformatics analysis suggested that the cGMP‐PKG pathway ranks as the first pathway enriched by the differential genes that correlated with DARS‐AS1 (|r| > 0.4). ATP1B2, as a cGMP‐PKG pathway‐related gene, was significantly correlated with the overall survival of CC patients. We further confirmed that ATP1B2 was lowly expressed in CC and negatively correlated with the DARS‐AS1 expression. Then, biological function experiments exhibited that the promotion of cell proliferation, invasion, and migration resulted due to the upregulation of DARS‐AS1 could be canceled by ATP1B2 overexpression. Finally, Western blot revealed that upregulation of DARS‐AS1 could activate the cGMP‐PKG pathway, while overexpression of ATP1B2 reversed this activation. Our study revealed that DARS‐AS1/ATP1B2 contributes to regulating the progression of CC at least partially by modulating the cGMP‐PKG pathway.

ASK1 Signaling in Cancer: Pathogenic Driver or Therapeutic Target?

ABSTRACT Apoptosis signal‐regulating kinase 1 (ASK1), an important member of the MAP kinase kinase kinase (MAP3K), has been identified as a significant modulator of cellular responses to oxidative stress, inflammatory responses, and endoplasmic reticulum stress. Structurally characterized by its thioredoxin‐binding domain, its kinase domain, and coiled‐coil structures, ASK1 relays downstream stimulation of JNK and p38 MAPK cascades. Yet, its role in cancer function is paradoxical and simultaneously serves as both a cancer inhibitor and an activator rely on cellular settings. In this article, an overview of the molecular biology of ASK1 is presented with emphasis on the elusive balance between stimulation and suppression by upstream molecules such as Trx, TRAF proteins, and ubiquitination machinery. We provide an overview of the dualistic role of ASK1 in cancer pathophysiology showing how its dysregulation leads to tumor development, metastasis, chemoresistance, or tumor suppression by pro‐apoptotic signals, respectively. An example of context‐dependent action is provided using the examples of different cancers including lung, breast, ovarian, and hepatocellular carcinoma. Moreover, we discuss new therapeutic approaches to ASK1 such as small‐molecule inhibitors, RNA therapies, and protein‐protein interaction modulation and speculate on their potential in personalized medicine. The article also deals with future opportunities in the sense of the bivalent character of ASK1 in developing context‐dependent and targeted cancer therapies. The key to unlocking the potential of ASK1 to be used as a therapeutic intervention and overcome the complications that are posed by its dualistic nature in cancer biology lie in the understanding of the complex regulatory network it forms.

Olaparib Triggers Mitochondrial Fission Through the CDK5/Drp‐1 Signaling Pathway in Ovarian Cancer Cells

ABSTRACT Ovarian cancer (OC) is the leading cause of death from gynecological malignancies worldwide. Alterations in mitochondrial metabolism are considered defining characteristics and therapeutic targets of OC. Olaparib, an oral inhibitor of poly (ADP‐ribose) polymerase, has been approved for the treatment of OC. However, the precise mechanisms by which it exerts its effects remain unclear. In this study, we uncover a novel pharmacological function of Olaparib by demonstrating that it induces mitochondrial dysfunction in human SKOV3 ovarian cancer cells. Our findings revealed that Olaparib exposure induced mitochondrial oxidative stress by elevating mitochondrial ROS levels and diminishing GPx activity. Additionally, treatment with Olaparib led to mitochondrial dysfunction, as evidenced by decreased complex I and complex IV activity and reduced ATP production. We observed that Olaparib induced mitochondrial fission by decreasing the average length of mitochondria. Olaparib did not affect the levels of Mfn1, Mfn2, or the total expression of Drp‐1. Intriguingly, Olaparib increased the levels of phosphorylated Drp‐1 at Ser616. Further investigation revealed that Olaparib facilitated the activation of the CDK5 signaling pathway and induced Caspase 3 activation. Notably, inhibition of CDK5 signaling using roscovitine mitigated the effects of Olaparib on mitochondrial fission and dysfunction, indicating a role for CDK5 in this process. In summary, our research identifies that CDK5/Drp‐1‐mediated mitochondrial fission may represent a novel mechanism through which Olaparib exerts its anticancer effects in OC.

TWIST1 Regulates FOXM1/β‐Catenin to Promote the Growth, Migration, and Invasion of Ovarian Cancer Cells by Activating MFAP2

ABSTRACTTWIST1 is aberrantly expressed in ovarian cancer (OC). MFAP2 is a downstream target of TWIST1, and we previously found MFAP2 facilitated OC development by activating FOXM1/β‐catenin. We planned to investigate the mechanisms of TWIST1 in OC. GEPIA (a database for gene expression analysis) and UALCAN (a database containing comprehensive cancer transcriptome and clinical patient data) investigated TWIST1's connection to MFAP2 and patient survival in ovarian serous cystadenocarcinoma (OV). Human OC cells (A2780 and CAOV3) were transfected with si‐TWIST1, oe‐TWIST1, oe‐MFAP2, or si‐TWIST1 + oe‐MFAP2. Cellular apoptosis, viability, migration, and invasion were detected. TWIST1, MFAP2, FOXM1, and β‐catenin protein expressions were tested. Dual‐luciferase and ChIP‐qPCR validated the correlation between MFAP2 and TWIST1. Moreover, OC mice were established by injecting OC cells subcutaneously. The pathology, apoptosis, as well as Ki67, TWIST1, MFAP2, FOXM1, and β‐catenin protein levels of tumors were assessed. TWIST1 expression positively correlated with MFAP2 expression, but negatively related to patients' survival in OV. TWIST1 overexpression promoted malignant behaviors, and increased MFAP2, FOXM1, and β‐catenin protein levels for OC cells. TWIST1 knockdown exhibited the opposite trend. In vivo, TWIST1 knockdown disrupted tissue structure, induced apoptosis, decreased Ki67, TWIST1, MFAP2, FOXM1, and β‐catenin protein levels in tumor. Interestingly, MFAP2 overexpression reversed the effects of TWIST1 knockdown in vitro and in vivo. Additionally, dual‐luciferase and ChIP‐qPCR confirmed MFAP2 was a downstream target for TWIST1 in OC. TWIST1 regulated FOXM1/β‐catenin to promote the growth, migration, and invasion of OC cells by activating MFAP2, indicating that targeting TWIST1 may be effective for treating OC.

Exome sequencing identifies ADGRG4 G‐protein‐coupled receptors gene as a novel cancer biomarker in ovarian cancer patients from North India

AbstractAdhesion G protein‐coupled receptor G4 (ADGRG4) is a G protein‐coupled receptor (GPCR) that belongs to the adhesion family. Participation of ADGRG4 in cell adhesion and migration, signaling pathway activation, influence on angiogenesis, and modulation of immune responses are some of the possible ways through which it may contribute to oncogenesis. Conducting extensive omics studies poses budgetary challenges to small labs in peripheral areas, primarily due to restricted research funding and resource limitations. Here we propose a low‐budget model for biomarker screening. A total of 11 ovarian cancer samples were sent for exome sequencing. Among various genes, ADGRG4 variants were present in all 11 samples and thus were chosen as a potential biomarker in the present population. However, the precise role of ADGRG4 in cancer is not fully understood. The present study aims to look at the association between the ADGRG4 gene variants and their risk of ovarian cancer in the North Indian region of Jammu and Kashmir, India. Overall, 235 individuals (115 cases and 120 healthy controls) were genotyped for the selected biomarker using Sanger sequencing. Logistic regression was used to assess the relationship between the variant and ovarian cancer. A statistically significant association was identified between the ADGRG4 variant rs5930932 polymorphism and the incidence of ovarian cancer among the study population. When corrected for age and BMI, the dominating OR of variant rs5930932 was 1.035 (1.003−1.069) under HWE patients (0.95) and controls (0.18), with a p‐value of (0.03). According to the findings of the current investigation, the ADGRG4 gene variant rs5930932 increases the chance of developing ovarian cancer in the studied population.

Low‐density lipoprotein receptor‐related protein 5/6 promotes endometrial cancer progression and cancer cell immune escape

AbstractThe study investigated the potential association of the low‐density lipoprotein (LDL) genome with endometrial cancer progression based on the Gene Expression Omnibus data set and The Cancer Genome Atlas data set. Differential and weighted gene coexpression network analysis was performed on endometrial cancer transcriptome datasets GSE9750 and GSE106191. The protein‐protein interaction network was built using LDL‐receptor proteins and the top 50 tumor‐associated genes. Low‐density lipoprotein‐related receptors 5/6 (LRP5/6) in endometrial cancer tissues were correlated with oncogenes, cell cycle‐related genes, and immunological checkpoints using Spearman correlation. MethPrimer predicted the LRP5/6 promoter CpG island. LRP2, LRP6, LRP8, LRP12, low‐density lipoprotein receptor‐related protein‐associated protein, and LRP5 were major LDL‐receptor‐related genes associated with endometrial cancer. LRP5/6 was enriched in various cancer‐related pathways and may be a key LDL‐receptor‐related gene in cancer progression. LRP5/6 may be involved in the proliferation process of endometrial cancer cells by promoting the expression of cell cycle‐related genes. LRP5/6 may be involved in the proliferation of endometrial cancer cells by promoting the expression of cell cycle‐related genes. LRP5/6 may promote the immune escape of cancer cells by promoting the expression of immune checkpoints, promoting endometrial cancer progression. The MethPrimer database predicted that the LRP5/6 promoter region contained many CpG islands, suggesting that DNA methylation can occur in the LRP5/6 promoter region. LRP5/6 may aggravate endometrial cancer by activating the phosphoinositide 3‐kinase/protein kinase B pathway.

WTAP Interferes With Ferroptosis by Regulating the m6A Modification of SF3B1 to Mediate the Malignant Progression of Endometrial Cancer

ABSTRACT Endometrial cancer (EC) poses a great threat to women's health worldwide. Splicing factor 3B, subunit 1 (SF3B1) and the methyltransferase Wilms tumor 1‐associated protein (WTAP) have been confirmed to be involved in the progression of EC, but the relationship between them and whether they jointly regulate EC is still unclear. The mRNA and protein levels of SF3B1 and WTAP were analyzed by qRT‐PCR and western blot. Then, cell proliferation, apoptosis, migration, and invasion behaviors were assessed by EdU, flow cytometry, wound healing, and Transwell assays. Bioinformatics tools were applied to predict the binding sites of WTAP on SF3B1 mRNA and the correlation between WTAP and SF3B1. The binding of the two and the m6A methylation level of SF3B1 were verified by RIP and MeRIP. Finally, the effect of WTAP/SF3B1 on EC tumors in vivo was determined by a xenograft tumor model. SF3B1 was highly expressed in EC and its knockdown inhibited the proliferation, expedited apoptosis, repressed migration and invasion, and promoted ferroptosis of EC cells. Besides, WTAP bound to SF3B1‐bound mRNA and induced its m6A methylation modification. Overexpression of WTAP accelerated the malignant progression of EC cells and restrained ferroptosis. Interestingly, overexpression of SF3B1 completely abolished the tumor suppressive effect induced by WTAP knockdown. WTAP stimulated tumor growth in vivo and suppressed ferroptosis by stabilizing SF3B1 expression. In conclusion, WTAP effectively suppressed ferroptosis in EC cells by modulating SF3B1 via m6A methylation, thereby aggravating EC.

Progress in the Research of Cuproptosis and Possible Targets for Gynecological Cancers

ABSTRACT Cuproptosis is a regulated, copper‐dependent form of cell death driven by mitochondrial protein lipoylation and disruption of the tricarboxylic acid (TCA) cycle. Increasing evidence in gynecologic oncology indicates that copper transport, lipoate metabolism, and respiratory‐chain phosphorylation influence tumor fitness and treatment response. This review evaluates cuproptosis as a therapeutic hypothesis across gynaecologic cancers and outlines actionable targets and strategies based on this mechanism. Mechanistically, ferredoxin 1 (FDX1)‐mediated lipoylation enables copper excess to precipitate TCA enzyme‐dependent proteotoxic stress that is distinct from apoptosis and ferroptosis. Therapeutic concepts arising from this biology include modulation of copper flux with ionophores or chelators, inhibition of lipoic acid synthases, and disruption of mitochondrial proteostasis. Clinically, cuproptosis‐related transcriptional signatures and imaging markers of mitochondrial respiration may help stratify patients for combination regimens that incorporate poly (ADP‐ribose) polymerase inhibitors, anti‐angiogenic agents, or immune checkpoint blockade. By synthesizing available mechanistic and translational evidence and highlighting trials‐ready strategies, this review positions cuproptosis as a tractable, precision‐oriented pathway for ovarian, cervical, and endometrial cancers.

Estrogen Promotes the Proliferation and Migration of Endometrial Cancer Through the GPER‐Mediated NOTCH Pathway

ABSTRACTThis study aims to investigate the expression of GPER in EC, assess the impact of estrogen on the proliferation and migration of EC via GPER, and examine the potential role of GPER in mediating the NOTCH pathway to influence EC proliferation and migration. The expression of GPER and its correlation with clinicopathological features were investigated using clinical data. Cell proliferation was assessed through MTT and EdU assays, while cell migration ability was evaluated using wound healing and transwell assays. Western blot analysis was conducted to detect proteins associated with the GPER and NOTCH signaling pathways. Additionally, xenograft tumor models were established to investigate the potential role of estrogen in mediating the NOTCH pathway via GPER. The results demonstrated a significant upregulation of GPER expression in EC, which was associated with clinical stage and metastasis. In vitro experiments provided evidence that estrogen promotes EC cell proliferation and metastasis by enhancing the expression levels of GPER, Notch1, and Hes‐1 proteins. Conversely, knocking down or suppressing GPER effectively reverses these effects. Furthermore, treatment with JAG‐1, an agonist for the NOTCH pathway, counteracts si‐GPER's inhibitory impact on both proliferation and migration abilities of EC cells while increasing Notch1 and Hes‐1 protein expression levels; however, it does not alter GPER expression. In vivo experiments have substantiated that estrogen facilitates EC proliferation via the GPER‐mediated NOTCH pathway.

Fucoxanthin prevents cell growth and induces apoptosis in endometrial cancer HEC‐1A cells by the inhibition of the PI3K/Akt/mTOR pathway

AbstractEndometrial cancer is the major type of gynecological cancer and ranks as the sixth most common cancer in women. Endometrial cancer usually is diagnosed in an advanced stage, complicating the treatments in many cases. The present research was focused on unveiling the in vitro anticancer role of fucoxanthin against the endometrial cancer HEC‐1A cells by inhibiting the phosphatidylinositol‐3‐kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling axis. The cytotoxicity of fucoxanthin against the endometrial cancer HEC‐1A cells was studied using the MTT test. The level of reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP) status, and apoptotic cell death in the 7.5 and 10 µM administered HEC‐1A cells were assayed using fluorescent staining techniques. The messenger RNA expression was analyzed using RT‐PCR for PI3K/Akt/mTOR signaling molecules, proapoptotic (Bax and caspase‐3) antiapoptotic (cyclin D1 and Bcl‐2) genes, and inflammatory markers like tumour necrosis factor α (TNFα), nuclear factor kappa B (NF‐κB), Cox‐2, and interleukin (IL)‐6. The cell viability assay proved that fucoxanthin effectively prevented HEC‐1A cell viability, where the IC50 was 7.5 µM. Fucoxanthin at 7.5  and 10 µM remarkably improved ROS production and apoptosis and decreased the MMP in HEC‐1A cells. The fucoxanthin effectively inhibited the PI3K/Akt/mTOR cascade along with the expression of TNF‐α, NF‐κB, Cox‐2, and IL‐6 and antiapoptotic genes cyclin D1 and Bcl‐2 in the HEC‐1A cells. Fucoxanthin treatment also enhanced the Bax and caspase‐3 expressions in the HEC‐1A cells. Our results from this work unveiled that fucoxanthin triggered growth inhibition and apoptosis in endometrial cancer HEC‐1A cells. Besides, fucoxanthin inhibited the PI3K/Akt/mTOR cascade and improved apoptotic marker expressions in the HEC‐1A cells.

Doxazosin and erlotinib have anticancer effects in the endometrial cancer cell and important roles in ERα and Wnt/β‐catenin signaling pathways

AbstractERα and Wnt/β‐catenin pathways are critical for the progression of most endometrial cancers. We aimed to investigate the cytotoxic and apoptotic effects of tamoxifen and quinazoline derivative drugs of doxazosin and erlotinib, and their roles in ERα and Wnt/β‐catenin signaling pathways in human endometrial cancer RL 95‐2 cell. 3‐(4,5‐Dimethylthiazol‐2yl)−2,5‐diphenyltetrazolium bromide assay and xCELLigence systems were performed to evaluate cytotoxicity. Furthermore, apoptotic induction was tested by Annexin V analysis. Caspase‐3 and ‐9 activity and changes in the mitochondrial membrane potential were evaluated. The level of reactive oxygen species was measured by incubating with dichlorofluorescein diacetate. Protein ratios of p‐ERα/ERα, GSK3β/p‐GSK3β, and p‐β‐catenin/β‐catenin and expression levels of ESR1, EGFR, c‐Myc genes were evaluated to elucidate mechanisms in signaling pathways. We found that the tested drugs showed cytotoxic and apoptotic effects in the cells. Doxazosin significantly reduced ESR1 expression, slightly reduced the p‐β‐catenin/β‐catenin ratio and c‐Myc expression. Erlotinib significantly increased c‐Myc expression while significantly decreasing the p‐β‐catenin/β‐catenin and p‐ERα/ERα ratio, and ESR1 expression. However, we observed that the cells develop resistance to erlotinib over a certain concentration, suggesting that ERα, ESR1, EGFR, and c‐Myc may be a new target for overcoming drug resistance in the treatment of endometrial cancer. We also observed that erlotinib and doxazosin play an important role in the ERα signaling pathway and can act as potent inhibitors of PKA and/or tyrosine kinase in the Wnt/β‐catenin signaling pathway in RL 95‐2 cell. In conclusion, doxazosin and erlotinib may have a possible therapeutic potential in human endometrial cancer.

Anticancer Properties of Newly Synthesized Pyrrole Derivatives as Potential Tyrosine Kinase Inhibitors

ABSTRACT The anticancer activity of a series of newly synthesized pyrrole derivatives was systematically evaluated in HeLa cervical cancer cells, focusing on their potential as tyrosine kinase inhibitors and modulators of the mTOR signaling pathway. This study builds on our previous synthetic work by investigating the biological effects of seven structurally characterized compounds (d1–d7). Among them, compounds d1 and d3 exhibited the most potent cytotoxicity, with IC₅₀ values of 140.6 μM and 366.4 μM, respectively, after 48 h of treatment. Both compounds significantly impaired cell cycle progression—d1 induced S‐phase arrest, while d3 caused G1‐phase arrest—and markedly suppressed cell migration in wound healing assays. Mechanistically, these effects were accompanied by reduced phosphorylation of p70S6K (Thr389, Ser421/424) and increased p‐4EBP1, indicating inhibition of mTORC1 signaling. These findings suggest that d1 and d3 are promising lead compounds with dual antiproliferative and anti‐migratory activity in cervical cancer, mediated through modulation of the PI3K/Akt/mTOR axis.

Ketamine Induces Mitochondrial Fission and Dysfunction in Cervical Cancer Cells via RhoA‐Dependent DRP‐1 Activation

ABSTRACTMitochondrial fragmentation, which is closely linked to mitochondrial dysfunction, has emerged as a critical treatment target for cervical cancer. Ketamine, a well‐known anesthetic, has shown potential in cancer therapy by inducing cytotoxicity, impairing mitochondrial function, and promoting apoptosis in tumor cells. Notably, the regulatory role of ketamine in mitochondrial network dynamics remains unexplored in current scientific literature. In this study, we demonstrated that ketamine exerts significant cytotoxic effects on C33A cervical cancer cells, as evidenced by dose‐dependent increases in γ‐glutamyl transpeptidase (GGT) levels and lactate dehydrogenase (LDH) release, accompanied by a corresponding reduction in cell viability. At 100 μM, ketamine induces mitochondrial dysfunction, characterized by decreased Complex IV activity, mitochondrial membrane potential (MMP), and ATP production, along with mitochondrial fragmentation. Mechanistically, ketamine upregulates mitochondrial p‐Drp1 levels without altering total DRP‐1 and enhances the expression of CaMK II and RhoA, but not Rac1/Cdc42. Inhibition of RhoA, but not CaMK II, attenuates ketamine‐induced mitochondrial DRP‐1 activation, fragmentation, and dysfunction, suggesting that RhoA is a key mediator. These findings highlight ketamine's potential as a therapeutic agent targeting mitochondrial dynamics in cervical cancer.

METTL3‐mediated NFAT5 Upregulation Promotes Cervical Cancer Progression Through Enhancing the Mitochondrial Function by Transcriptional Regulation of PRDX1

ABSTRACTNuclear factor of activated T‐cells 5 (NFAT5) is recognized as an oncogene in a variety of tumors. However, the role of NFAT5 in cervical cancer (CC) cell phenotypic alterations remains to be elucidated. Here, we demonstrated that NFAT5 expression was elevated in CC samples and cells using quantitative real‐time reverse transcription PCR, Western blot analysis, and immunohistochemistry assays, and high NFAT5 expression showed a poor prognosis. After C‐33A cells were transfected with pcDNA‐NFAT5 or NFAT5‐short hairpin RNA (shRNA), cell proliferation, invasion, and apoptosis were evaluated using CCK‐8 and EdU assays, transwell assays, and flow cytometry, respectively. Biomarkers indicating mitochondrial function, including the expression of the d‐loop, ATP levels, and mitochondrial membrane potential, were detected. NFAT5 knockdown restrained cell proliferation and invasion, impaired mitochondrial function, and increased the ratio of cell apoptosis; however, NFAT5 overexpression showed the opposite results. RNA immunoprecipitation (RIP) and methylated RIP (MeRIP) assays were performed to identify interactions among NFAT5, methyltransferase‐like 3 (METTL3), and insulin‐like growth factor 2 mRNA‐binding protein 3 (IGF2BP3). Chromatin immunoprecipitation and dual‐luciferase reporter gene assays demonstrated that NFAT5 binds to the peroxiredoxin 1 (PRDX1) promoter to drive PRDX1 transcription. METTL3 enhanced NFAT5 mRNA stability through IGF2BP3‐mediated N6‐Methyladenosine (m6A) modification, and NFAT5 transcriptionally regulated PRDX1 expression. Moreover, the reintroduction of METTL3 or PRDX1 promoted cell growth and mitochondrial function damage in NFAT5‐silenced cells. In vivo experiments further demonstrated that NFAT5 promotes CC tumor growth. Taken together, NFAT5 upregulation mediated by the METTL3/IGF2BP3 complex in an m6A‐dependent manner facilitates CC cell growth by transcriptionally regulating PRDX1 expression, providing a novel target for CC therapy.

IGF2BP3 Knockdown Induces Ferroptosis by Inhibiting Autophagy‐Mediated EMC2 Degradation in Ovarian Cancer

ABSTRACT Recent studies have increasingly demonstrated that chemoresistance in ovarian cancer primarily stems from resistance to oxidative stress and ferroptosis. Ferroptosis, a non‐apoptotic form of cell death dependent on intracellular iron and marked by the buildup of lipid reactive oxygen species (ROS), has shown enhanced effectiveness in triggering cell death in ovarian cancer cells. Thus, this study aimed to explore the potential of gene knockdown associated with ferroptosis as an innovative therapeutic strategy against ovarian cancer. Up‐regulated genes were identified using a gene bank, and their expression levels were validated through Western blotting (WB) and quantitative PCR (qPCR). Levels of MDA, Fe 2+ , GSH, ROS, SQSTM1, LC3‐I and LC3‐II in ovarian cancer cells treated with sorafenib and subjected to gene knockout were assessed using specific kits. Expression levels of proteins related to ferroptosis were analyzed by WB. Tumor size, volume, ferroptosis and autophagy in ovarian cancer tumor tissues were also examined. IGF2BP3 was elevated in human ovarian cancer and decreased during ferroptosis induced by sorafenib in human ovarian cancer cells. IGF2BP3 knockdown inhibited ovarian cancer cell function and promoted ferroptosis, in addition to autophagy‐mediated EMC2 degradation. IGF2BP3 knockdown increased ovarian cancer sensitivity to sorafenib. This study confirmed that IGF2BP3 knockdown inhibited ovarian cancer cell malignancy, promoted ferroptosis and inhibited autophagy‐mediated EMC2 degradation, and verified that IGF2BP3 knockdown increased the sensitivity to sorafenib in ovarian cancer mice.

Circ_0005615 promotes cervical cancer cell growth and metastasis by modulating the miR‐138‐5p/KDM2A axis

AbstractCervical cancer (CC) is a highly fatal gynecological malignancy due to its high metastasis and recurrence rate. Circular RNA (circRNA) has been regarded as a regulator of CC. However, the underlying molecular mechanism of circ_0005615 in CC remains unclear. The levels of circ_0005615, miR‐138‐5p, and lysine demethylase 2A (KDM2A) were measured using qRT‐PCR or western blot. Cell proliferation was assessed by Cell Counting Kit‐8, 5‐ethynyl‐2′‐deoxyuridine, and colony formation experiments. Cell invasion and migration were tested by transwell assay and wound healing assay. Flow cytometry and Caspase‐Glo 3/7 Assay kit were used to analyze cell apoptosis. The expression of proliferation‐related and apoptosis‐related markers was detected by western blot. The binding relationships among circ_0005615, miR‐138‐5p, and KDM2A were verified by dual‐luciferase reporter assay or RNA immunoprecipitation assay. Xenograft assay was applied to detect the effect of circ_0005615 in vivo. Circ_0005615 and KDM2A were upregulated, while miR‐138‐5p was downregulated in CC tissues and cells. Circ_0005615 knockdown retarded cell proliferation, migration, and invasion, while promoting apoptosis. Besides, circ_0005615 sponged miR‐138‐5p, and miR‐138‐5p could target KDM2A. miR‐138‐5p inhibitor reversed the regulation of circ_0005615 knockdown on CC cell growth and metastasis, and KDM2A overexpression also abolished the inhibitory effect of miR‐138‐5p on CC cell growth and metastasis. In addition, we also discovered that circ_0005615 silencing inhibited CC tumor growth in vivo. Circ_0005615 acted as a tumor promoter in CC by regulating the miR‐138‐5p/KDM2A pathway.

Scutellarein induces apoptosis and inhibits proliferation, migration, and invasion in ovarian cancer via inhibition of EZH2/FOXO1 signaling

AbstractScutellarein, a flavone found in the perennial herb Scutellaria baicalensis, has antitumorigenic activity in multiple human cancers. However, whether scutellarein can attenuate ovarian cancer (OC) is unclear. This study investigated the effects of scutellarein in OC. In vitro cell viability was assessed using MTT assay whereas proliferation was assessed using 5‐ethynyl‐2′‐deoxyuridine and colony formation assays. Cell apoptosis was detected by an Annexin V‐fluorescein isothiocyanate/propidium iodide assay. Wound‐healing and Transwell assays were used to determine cell migration and invasion. The differential expression of enhancer of zeste homolog 2 (EZH2) and forkhead box protein O1 (FOXO1) was measured by Quantitative real‐time PCR and western blot analysis. We found that scutellarein inhibited viability, migration, invasion of A2780 and SKOV‐3 cells, and reduced the expression of EZH2 in OC cells. In addition, FOXO1 was downregulated in OC tissues and cells and negatively regulated by EZH2. Also, scutellarein inhibited tumor growth and metastasis in vivo. In conclusion, scutellarein alleviates OC by the regulation of EZH2/FOXO1 signaling.

Synthesis, docking studies, in vitro cytotoxicity evaluation and DNA damage mechanism of new tyrosine‐based tripeptides

AbstractPeptides are one of the leading groups of compounds that have been the subject of a great deal of biological research and still continue to attract researchers' attention. In this study, a series of tripeptides based on tyrosine amino acids were synthesized by the triazine method. The cytotoxicity properties of all compounds against human cancer cell lines (MCF‐7), ovarian (A2780), prostate (PC‐3), and colon cancer cell lines (Caco‐2) were determined by the 3‐[4,5‐dimethylthiazol‐2‐yl]‐2,5 diphenyl tetrazolium bromide assay method, and % cell viability and logIC50 values of the compounds were calculated. Significant decreases in cell viability were observed in all cells (p < 0.05). The comet assay method was used to understand that the compounds that showed a significant decrease in cell viability had this effect through DNA damage. Most of the compounds exhibited cytotoxicity by DNA damage mechanism. Besides, their interactions between investigated molecule groups with PDB ID: 3VHE, 3C0R, 2ZCL, and 2HQ6 target proteins corresponding to cancer cell lines, respectively, were investigated by docking studies. Finally, molecules with high biological activity against biological receptors were determined by ADME analysis.

Knockdown of circMFN2 inhibits cell progression and glycolysis by miR‐198/CUL4B pathway in ovarian cancer

AbstractCircular RNA (circRNA) regulates malignant tumors, including ovarian cancer (OC). The present research study aimed to reveal the biological mechanism of circRNA mitofusin 2 (circMFN2) in OC. Cell biological behaviors were investigated using clonogenicity assay, EdU assay, transwell assay, and flow cytometry analysis. Quantitative reverse transcription polymerase chain reaction (qRT‐PCR) and western blot analysis were implemented to detect the levels of circMFN2, miR‐198, Cullin 4B (CUL4B), and apoptosis‐related proteins. Glycolysis was assessed by glucose assay kit, lactate assay kit, and ATP level detection kit. The relationships among miR‐198, circMFN2, and CUL4B were verified by dual‐luciferase reporter assay and RNA immunoprecipitation assay. The xenograft mice model was used to analyze tumor growth in vivo. The expression of circMFN2 and CUL4B was increased, while miR‐330‐5p was decreased in OC tissues or cells. The absence of CircMFN2 hindered cell proliferation, migration, invasion, and glycolysis and promoted apoptosis in OC cells. We found that circMFN2 promoted CUL4B expression via sponging miR‐198. MiR‐198 depletion reversed circMFN2 knockdown‐induced effects in OC cells. Furthermore, CUL4B overexpression overturned the inhibitory effect of miR‐198 in OC cells. And the absence of circMFN2 inhibited tumor growth in vivo. CircMFN2 repressed OC progression by regulating the miR‐198/CUL4B axis.

Eriodictyol regulated ferroptosis, mitochondrial dysfunction, and cell viability via Nrf2/HO‐1/NQO1 signaling pathway in ovarian cancer cells

AbstractThis study aimed to investigate the antitumor effect and the underlying molecular mechanism of eriodictyol on ovarian cancer cells. CaoV3 and A2780 were exposed to eriodictyol at different concentrations of 0−800 μM. Cell apoptosis and viability were determined by TdT‐mediated dUTP Nick‐End Labeling (TUNEL) assay and Cell Counting Kit‐8 (CCK‐8) assay, respectively. Mitochondrial membrane potential was evaluated by flow cytometers with a JC‐1 detection kit. Fe2+ content was evaluated using an iron assay kit. The section of tumor tissues was observed using hematoxylin‐eosin (H&E) staining and nuclear factor erythroid 2‐related factor 2 (Nrf2) expression was detected by immunohistochemistry (IHC) staining. Eriodictyol suppressed cell viability and induced cell apoptosis of CaoV3 and A2780 cells. Half maximal inhibitory concentration (IC50) value of CaoV3 at 24 and 48 h was (229.74 ± 5.13) μM and (38.44 ± 4.68) μM, and IC50 value of A2780 at 24 and 48 h was (248.32 ± 2.54) μM and (64.28 ± 3.19) μM. Fe2+ content and reactive oxygen species production were increased and protein levels of SLC7A11 and GPX4 were decreased by eriodictyol. Besides, eriodictyol reduced the ratio of JC‐1 fluorescence ratio, glutathione and malondialdehyde contents but elevated Cytochrome C level. Nrf2 phosphorylation were obviously downregulated by eriodictyol. Finally, eriodictyol suppressed tumor growth, aggravated mitochondrial dysfunction and downregulated Nrf2 expression in tumor tissue in mice. Eriodictyol regulated ferroptosis, mitochondrial dysfunction and cell viability via Nrf2/HO‐1/NQO1 signaling pathway in ovarian cancer.

Diminazene aceturate‐induced cytotoxicity is associated with the deregulation of cell cycle signaling and downregulation of oncogenes Furin, c‐MYC, and FOXM1 in human cervical carcinoma Hela cells

AbstractDiminazene aceturate (DIZE) is an FDA‐listed small molecule known for the treatment of African sleeping sickness. In vivo studies showed that DIZE may be beneficial for a range of human ailments. However, there is very limited information on the effects of DIZE on human cancer cells. The current study aimed to investigate the cytotoxic responses of DIZE, using the human carcinoma Hela cell line. WST‐1 cell proliferation assay showed that DIZE inhibited the viability of Hela cells in a dose‐dependent manner and the observed response was associated with the downregulation of Ki67 and PCNA cell proliferation markers. DIZE‐treated cells stained with acridine orange‐ethidium and JC‐10 dye revealed cell death and loss of mitochondrial membrane potential (Ψm), compared with DMSO (vehicle) control, respectively. Cellular immunofluorescence staining of DIZE‐treated cells showed upregulation of caspase 3 activities. DIZE‐treated cells showed downregulation of mRNA for G1/S genes CCNA2 and CDC25A, S‐phase genes MCM3 and PLK4, and G2/S phase transition/mitosis genes Aurka and PLK1. These effects were associated with decreased mRNA expression of Furin, c‐Myc, and FOXM1 oncogenes. These results suggested that DIZE may be considered for its effects on other cancer types. To the best of our knowledge, this is the first study to evaluate the effect of DIZE on human cervical cancer cells.

Circ‐DTL sponges miR‐758‐3p to accelerate cervical cancer malignant progression by regulating DCUN1D1 expression

AbstractCircular RNAs (circRNAs) play important roles in regulating various cancer progression. However, the function and clinical significance of circ‐denticleless E3 ubiquitin proteinligase homolog (DTL) in cervical cancer (CC) have not been studied. The present work explored the function and mechanism of circ‐DTL in CC development. Quantitative real‐time polymerase chain reaction (qRT‐PCR) was performed to examine the expression of circ‐DTL, miR‐758‐3p, and DCUN1D1. Cell Counting Kit‐8 (CCK‐8) and 5‐ethynyl‐2′‐deoxyuridine (EdU) assays were used to detect cell proliferation. Cell cycle and cell apoptosis were investigated by flow cytometry. Wound‐healing assay and transwell assay were conducted to assess cell migration and cell invasion. Western blot assay was carried out to determine protein expression. Dual‐luciferase reporter assay and RNA immunoprecipitation (RIP) assay were used to identify the relationship between miR‐758‐3p and circ‐DTL or DCUN1D1. Xenograft mouse model assay was conducted to explore the role of circ‐DTL in CC progression in vivo. Circ‐DTL and DCUN1D1 expression were upregulated in CC tissues and CC cells, but miR‐758‐3p expression was downregulated. Knockdown of circ‐DTL inhibited CC cell growth, migration, and invasion and promoted cell cycle arrest and cell apoptosis. Circ‐DTL could sponge miR‐758‐3p to modulate CC cell progression. Moreover, miR‐758‐3p inhibited CC malignant development by suppressing DCUN1D1 expression. In addition, circ‐DTL knockdown repressed CC cell tumor properties in vivo. Circ‐DTL acted as a tumor promoter in CC development by regulating the miR‐758‐3p/DCUN1D1 pathway.

17β‐Estradiol via Orai1 activates calcium mobilization to induce cell proliferation in epithelial ovarian cancer

AbstractEpithelial ovarian cancer (EOC) is the most lethal estrogen‐sensitive gynecological cancer. Studies have reported that estrogen induces rapid cellular calcium mobilization in cells and can determine the fate of a cell. We found that estrogen increased the calcium release‐activated calcium channel modulator 1 (Orai1) protein expression levels in SK‐OV‐3 cells. However, to date, there has been no research on the functional relationship and molecular mechanism of estrogen‐regulating Orai1 during EOC development. In our study, Orai1 had a high expression level in high‐grade serous ovarian tumor tissues and SK‐OV‐3 cells. Estrogen promoted cell proliferation and migration while inhibiting cell apoptosis in SK‐OV‐3 cells. Orai1 silencing suppressed estrogen‐induced cell migration and proliferation. Overexpression of Orai1, however, enhanced the ability of 17β‐estradiol (E2) to exert its function. Estrogen induced rapid calcium influx in SK‐OV‐3 cells. Knockdown of Orai1 in SK‐OV‐3 cells blocked E2‐induced stored‐operated Ca2+ influx. The messenger RNA expression of caspase 3, matrix metallopeptidase 1, and cyclin‐dependent kinase 6 were regulated via Orai1 under E2 treatment. Our results suggest that estrogen, by regulating Orai1, induced calcium influx to determine cell fate.

Research Progress of Proteasome Inhibitor MG132 in Treatment of Gynecologic Malignant Tumors

ABSTRACT The ubiquitin‐proteasome system (UPS) is the primary mechanism for intracellular protein degradation, crucial in oncogenesis and tumor progression. Proteasome inhibitors disrupt UPS‐mediated proteolysis, effectively inhibiting neoplastic cell proliferation, and have become established therapeutic targets in oncology. Gynecologic malignant tumors pose a significant threat to women's reproductive health globally. Among proteasome inhibitors, MG132 has garnered extensive attention in gynecologic oncology due to its multifaceted mechanisms, including cell cycle regulation, NF‐κB signaling inhibition, and modulation of p53 activity. This review consolidates recent research on the therapeutic potential of MG132 in gynecologic malignant tumors, with a focus on its molecular mechanisms of action.