International Journal of Biological Sciences

The IFN-γ-IDO1-kynureine pathway-induced autophagy in cervical cancer cell promotes phagocytosis of macrophage

Suppressing MDSC Infiltration in Tumor Microenvironment Serves as an Option for Treating Ovarian Cancer Metastasis

It is still a big puzzle how ovarian cancer cells and the tumor microenvironment (TME) attract lymphocytes infiltration for facilitating metastasis, a leading cause of death from gynecological malignancies. Using genome-wide LncRNA microarray assay, here we report that a LncRNA associated with ovarian cancer metastasis (LncOVM) is highly correlated with poor prognosis and survival. LncOVM interacts with and stabilizes PPIP5K2 by suppressing ubiquitinated degradation to promote complement C5 secretion from ovarian cancer cells. The TME-enriched complement C5 attracts myeloid-derived suppressor cells (MDSCs) infiltration in TME to facilitate metastasis. Knockdown of LncOVM or PPIP5K2 inhibits tumor progression in xenograft models. Application of C5aR antibody or inhibitor (CCX168) inhibits MDSC recruitment and restores the suppression of tumorigenesis and metastasis

Inhibition of PKM2 Enhances Sensitivity of Olaparib to Ovarian Cancer Cells and Induces DNA Damage

Poly (ADP-ribose) polymerase inhibitors (PARPi) have showed clinical benefit as maintenance therapy in advanced ovarian cancer by impairing the homologous recombination (HR) pathway. Pyruvate kinase M2 (PKM2), the significant cancer metabolic biomarker, integrates with DNA damage to directly promote HR. We aimed to investigate the role and molecular mechanism of PKM2 downregulation on sensitization of ovarian cancer cells to PARPi. Inhibitory effects in vitro were assessed by cell viability, clone formation, transwell assay, and flow cytometry. Downregulation of PKM2 by siRNA or small molecular inhibitor shikonin (Sk) enhanced anti-tumour activity of olaparib (Ola) in ovarian cancer cells. Silencing PKM2 or Sk synergized with Ola and reduced cell growth, colony formation and migration, and induced apoptosis. Western blot and immunofluorescence demonstrated that inhibition of PKM2 amplified Ola-induced γH2AX and phospho-ATM (p-ATM) activation and interfered with BRCA1 accumulation in the nucleus. A xenograft animal model demonstrated in vivo antitumor combination effect of Sk and Ola. Furthermore, Western blot and immunofluorenscent analyses of tissue samples revealed that treatment of Sk increased DNA damage, reduced expression of BRCA1 and PKM2. Therefore, this study identified that PKM2 downregulation is a novel therapeutic strategy to enhance Ola effectiveness in treating ovarian cancer.

HJURP Promotes Malignant Progression and Mediates Sensitivity to Cisplatin and WEE1-inhibitor in Serous Ovarian Cancer

Ovarian cancer is the most lethal gynecological malignancy. Recurrence and chemoresistance are tough challenges leading to poor prognosis. HJURP is a molecular chaperone of CENP-A, which is associated with aggressive progression in multiple tumors. However, the function of HJURP in ovarian cancer has not been elucidated. In our study, we found HJURP was over-expressed in ovarian cancer and high expression of HJURP was correlated to unfavorable prognosis. HJURP knockdown could inhibit proliferation, metastasis and induce G0/G1 stagnation of ovarian cancer cells. Besides, next-generation sequencing (NGS) unveiled that WEE1 was down-regulated by silencing HJURP. Further mechanistic research revealed that HJURP regulated WEE1 through MYC, and luciferase assay indicated that MYC was a transcription factor of WEE1. Additionally, we investigated that silencing HJURP increased sensitivity of ovarian cancer cells to cisplatin via MYC/WEE1 axis, and HJURP participated in DNA repair of cisplatin-induced damage. More interestingly, silencing HJURP could enhance sensitivity of ovarian cancer cells to AZD1775 and improve the synergistic effect of cisplatin plus AZD1775 combined therapy. Collectively, our data displays that HJURP promotes tumor progression and chemoresistance of ovarian cancer, and HJURP has potential to be a novel therapeutic target in the combined treatment with cisplatin and AZD1775 in ovarian cancer.

IU1 suppresses proliferation of cervical cancer cells through MDM2 degradation

Previous studies have demonstrated that the antitumor potential of IU1 (a pharmacological compound), which was mediated by selective inhibition of proteasome-associated deubiquitinase ubiquitin-specific protease 14 (USP14). However, the underlying molecular mechanisms remain elusive. It has been well established that

LRP1B mutation is associated with tumor HPV status and promotes poor disease outcomes with a higher mutation count in HPV-related cervical carcinoma and head & neck squamous cell carcinoma

Human papillomavirus (HPV) infection and gene mutations were reputed as key factors in cervical carcinoma (CC) and head and neck squamous cell carcinoma (HNSCC). However, the associations of HPV status and gene mutations remain to be determined. This study aims to identify molecular patterns of

E2F8 regulates the proliferation and invasion through epithelial-mesenchymal transition in cervical cancer

The transcription factor E2F is an important modulator of the cell cycle, and the unrestricted activation of E2F-dependent transcription is considered to be an important driver of tumor formation and progression. E2F8 is known to play an important role in embryonic development and cell cycle control by inhibiting E2F1. However, it is not yet known whether E2F8 is involved in the progression of cervical cancer. In this study, the functional consequences of E2F8 knockdown

NK-92MI Cells Engineered with Anti-claudin-6 Chimeric Antigen Receptors in Immunotherapy for Ovarian Cancer

A novel CSN5/CRT O-GlcNAc/ER stress regulatory axis in platinum resistance of epithelial ovarian cancer

CircCLMP Suppresses Anti-Tumor Immunity by Inhibiting Activation of IRF3 and Interferon Response in Microsatellite Instability-high Endometrial Cancer

Immune checkpoint inhibitors have been proven effective for recurrent or metastatic cases of microsatellite instability-high (MSI) endometrial cancer (EC). However, drug resistance exists in a noticeable proportion of patients. Elucidating the underlying mechanisms would help develop new therapeutic strategies and benefit in improving patients' prognosis. Circular RNAs (circRNAs) are excellent biomarkers due to their stability and tissue specificity. Evidence has showed that circRNAs could mediate immune evasion in several types of malignancies. However, whether they regulate the immune response in MSI EC has not been explored. Here, based on the results of our former circRNA array, which identified the differentially-expressed circRNAs in MSI EC, we found that a circRNA, circCLMP, was negatively correlated with CD8

ARID1A deficiency activates OSM-STAT3 axis in endometrial cancer, creating vulnerability to JAK/STAT3 inhibition

ARID1A, a key component of the SWI/SNF chromatin remodeling complex, is a tumor suppressor frequently inactivated in many cancer types, including endometrial cancer. Exploiting ARID1A deficiency has emerged as a therapeutic strategy in these types of cancer. We here employed a synthetic lethal drug screen for ARID1A and found that JAK/STAT3 pathway is a therapeutic vulnerability in ARID1A-deficient endometrial cancer. Inhibition of JAK/STAT3 selectively inhibited the growth of ARID1A deficient endometria cancer cells

Novel LncRNA LINC02936 Suppresses Ferroptosis and Promotes Tumor Progression by Interacting with SIX1/CP Axis in Endometrial Cancer

Endometrial cancer (EC) is a prevalent gynecological malignancy, and metabolic disorders are among its most significant risk factors. Abnormal iron metabolism is associated with the progression of cancer malignancy. Nevertheless, the involvement of iron metabolism in the EC remains uncertain. Ceruloplasmin (CP) functions as a multicopper oxidase and ferroxidase, playing a crucial role in maintaining the metabolic balance between copper and iron. Prior research has demonstrated that the dysregulated expression of CP has important clinical implications in EC. However, ​the specific underlying molecular mechanisms remains uncertain. This research examined the impact of CP on the malignant advancement of EC by suppressing ferroptosis. Next, we explored the possibility that Long non-coding RNA (lncRNA) LINC02936/SIX1/CP axis may be a key pathway for inhibiting ferroptosis and promoting cancer progression in EC. Mechanistically, SIX1 modulates the expression of CP, whereas LINC02936 interacts with SIX1 and recruits SIX1 to the CP promoter, leading to upregulation of CP, inhibition of ferroptosis, and promotion of EC progression. Administration of a small peptide cloud block the LINC02936-SIX1 interaction, thereby inhibits EC progression by promoting ferroptosis. Altogether, this is the first report on the lncRNA regulation of ferroptosis in EC. Our research enhances the knowledge of the lncRNA-mediated regulation of ferroptosis in EC progression and indicates the potential therapeutic significance of the LINC02936/SIX1/CP axis in treating EC.

Dual-Multivalent Aptamer-Based Drug Delivery Platform for Targeted SRC Silencing to Enhance Doxorubicin Sensitivity in Endometrial Cancer

Endometrial cancer poses a significant threat to women's health. Doxorubicin is commonly used in chemotherapy for advanced and recurrent cases; however, low sensitivity frequently limits its effectiveness. In this study, we verified that SRC modulates the sensitivity of endometrial cancer to chemotherapy of doxorubicin and developed a targeted silencing drug delivery platform that employs rolling circle amplification and dual-multivalent aptamers to precisely deliver therapeutics directly to tumor cells. This platform enhanced endometrial cancer cell sensitivity to doxorubicin by modulating drug responsiveness at the genetic level. Our results suggest that this approach may improve cancer cell susceptibility to ferroptosis. The efficacy and safety of this platform were validated in both cellular and animal models. This study provides a new solution for realizing the precision treatment of endometrial cancer and lays a theoretical foundation for exploring the mechanism of endometrial cancer.

Endometrial Stem Cells: Orchestrating Dynamic Regeneration of Endometrium and Their Implications in Diverse Endometrial Disorders

The human endometrium, a vital component of the uterus, undergoes dynamic changes during the menstrual cycle to create a receptive environment for embryo implantation. Its remarkable regenerative capacity can be attributed to the presence of tissue-resident stem cell populations within the endometrium. Despite variations in characteristics among different subtypes, endometrial stem cells exhibit notably robust self-renewal capacity and the ability to differentiate into multiple lineages. This review offers a comprehensive insight into the current literature and recent advancements regarding the roles of various endometrial stem cell types during dynamic regeneration of the endometrium during the menstrual cycle. In addition, emerging evidence suggests that dysfunction or depletion of endometrial stem cells may play critical roles in the development and progression of various endometrial disorders, such as endometriosis, uterine fibroids, adenomyosis, infertility, and endometrial cancer. Therefore, we also highlight potential roles of endometrial stem cells in the development and progression of these endometrial diseases, including their ability to accumulate genetic mutations and express genes associated with endometrial diseases. Understanding the dynamic properties of the endometrium and the roles of endometrial stem cells in various endometrial disorders will shed light on potential therapeutic strategies for managing these conditions and improving women's fertility outcomes.

EXOSC5 maintains cancer stem cell activity in endometrial cancer by regulating the NTN4/integrin β1 signalling axis

Endometrial carcinoma (EC) is a common type of uterine cancer in developed countries, originating from the uterine epithelium. The incidence rate of EC in Taiwan has doubled from 2005. Cancer stem cells (CSCs) are a subpopulation of cancer cells that have high tumorigenicity and play a crucial role in the malignant processes of cancer. Targeting molecules associated with CSCs is essential for effective cancer treatments. This study delves into the role of Exosome component 5 (EXOSC5) in EC. Data from The Cancer Genome Atlas suggests a correlation between high EXOSC5 mRNA expression and unfavorable EC prognosis. EXOSC5 knockdown diminished EC-CSC self-renewal and reduced expression of key cancer stemness proteins, including c-MYC and SOX2. Intriguingly, this knockdown significantly curtailed tumorigenicity and CSC frequency in EC tumor spheres. A mechanistic examination revealed a reduction in netrin4 (NTN4) levels in EXOSC5-depleted EC cells. Moreover, NTN4 treatment amplified EC cell CSC activity and, when secreted, NTN4 partnered with integrin β1, subsequently triggering the FAK/SRC axis to elevate c-MYC activity. A clear positive relation between EXOSC5 and NTN4 was evident in 93 EC tissues. In conclusion, EXOSC5 augments NTN4 expression, activating c-MYC via the integrin β1/FAK/SRC pathway, offering potential avenues for EC diagnosis and treatment.

FBXW7 Directly Ubiquitinates and Degrades CTNNB1 Mediating the Suppression of ENKUR in Endometrial Cancer

Enkurin (ENKUR) is a tumor suppressor in some malignancies. However, its role in endometrial cancer (EC) remains unknown. Here, we firstly observed that reduced ENKUR expression promotes progression and poor prognosis in EC. Moreover,the overexpression of ENKUR suppressed the proliferation, migration, invasion, and intrahepatic dissemination of EC

High-dose Ascorbate Exhibits Anti-proliferative and Anti-invasive Effects Dependent on PTEN/AKT/mTOR Pathway in Endometrial Cancer in vitro and in vivo

Endometrial cancer (EC) is the most common gynecological malignancy, frequently characterized by PTEN deletion, activation of the AKT/mTOR pathway, and limited effective treatment options for recurrent and advanced patients. High-dose ascorbate or combined with other chemotherapeutic agents shows potent antitumor effects

TBK1 inhibitor amlexanox exerts anti-cancer effects against endometrial cancer by regulating AKT/NF-κB signaling

Endometrial cancer, a common gynecological malignancy, poses significant clinical challenges, particularly in advanced or recurrent cases. TANK-binding kinase 1 (TBK1), a serine/threonine kinase, plays crucial roles in inflammation and immunity by activating nuclear factor (NF)-κB and interferon regulatory factor 3. However, its specific roles in endometrial cancer remain unknown. In this study, we aimed to investigate the anti-cancer effects and underlying mechanisms of amlexanox, a TBK1 inhibitor, against endometrial cancer. The main genetic mutations in TBK1 were found to be mRNA downregulation and missense mutations. Kaplan-Meier plotter analysis revealed that low TBK1 expression was associated with a good prognosis in patients with uterine corpus endometrial carcinoma (UCEC).

Calcium and calcium-related proteins in endometrial cancer: opportunities for pharmacological intervention

Intracellular calcium ions are key second messengers and play an important role in malignant transformation and cancer progression. Estrogen can evoke intracellular calcium increases through membrane-initiated effects and activate subsequent kinase cascades within minutes in normal and cancerous epithelial cells. Ca

Development of a novel immune-related lncRNA signature as a prognostic classifier for endometrial carcinoma

Endometrial carcinoma (EnCa) is one of the deadliest gynecological malignancies. The purpose of the current study was to develop an immune-related lncRNA prognostic signature for EnCa. In the current research, a series of systematic bioinformatics analyses were conducted to develop a novel immune-related lncRNA prognostic signature to predict disease-free survival (DFS) and response to immunotherapy and chemotherapy in EnCa. Based on the newly developed signature, immune status and mutational loading between high‑ and low‑risk groups were also compared. A novel 13-lncRNA signature associated with DFS of EnCa patients was ultimately developed using systematic bioinformatics analyses. The prognostic signature allowed us to distinguish samples with different risks with relatively high accuracy. In addition, univariate and multivariate Cox regression analyses confirmed that the signature was an independent factor for predicting DFS in EnCa. Moreover, a predictive nomogram combined with the risk signature and clinical stage was constructed to accurately predict 1-, 2-, 3-, and 5-year DFS of EnCa patients. Additionally, EnCa patients with different levels of risk had markedly different immune statuses and mutational loadings. Our findings indicate that the immune-related 13-lncRNA signature is a promising classifier for prognosis and response to immunotherapy and chemotherapy for EnCa.

A Real-World Study on Diagnosis and Treatment of Uterine Sarcoma in Western China

Uterine sarcomas constitute a rare heterogeneous group of gynecological malignancies with aggressive characteristics and poor prognosis. They have similar clinical features to benign leiomyomata making them difficult to reliably identify prior to hysterectomy. The preoperative prediction of uterine sarcoma remains a clinical dilemma. The current study conducted a multicentre, retrospective study to examine the accuracy of preoperative diagnosis, the consequent influence on therapy, and survival factors in patients with uterine sarcoma in Western China. Four affiliated hospitals of the medical college in Western China over a six-year period. One hundred and fourteen patients diagnosed with low-grade endometrial stromal sarcoma (LG-ESS), high-grade endometrial stromal sarcoma (HG-ESS), undifferentiated uterine sarcoma (UUS), leiomyosarcoma (LMS), or adenosarcoma (AS) were analyzed. The median age at diagnosis was 47 years. Eighty (70.2%) patients were premenopausal and 34 (29.8%) post-menopausal. The most common pathological type was LG-ESS (43.9%). The diagnostic sensitivity of ultrasound for uterine malignant tumors was 11.0%, much lower than MRI (35.3%) and CT (63.0%). Unlike MRI, most of the patients who underwent CT (88.2%) examination were at the advanced stage. Forty-seven (41.2%) patients with uterine sarcoma were diagnosed with uterine malignant tumor before operation. Thirty-two (47.8%) patients who were misdiagnosed before operation needed reoperation and five patients (4.6%) diagnosed after radical surgery developed distant metastasis simultaneously. The recommended treatment of 87.0% of the patients with uterine sarcoma was total hysterectomy and bilateral salpingooophorectomy, and 53.7% of patients received adjuvant chemotherapy after operation. Pelvic lymph node status were clarified in 47 patients (43.5%), which were higher in HG-ESS and UUS groups, and lower in LMS group (

Long non-coding RNA steroid receptor activator promotes the progression of endometrial cancer via Wnt/ β-catenin signaling pathway

SERINC2-mediated serine metabolism promotes cervical cancer progression and drives T cell exhaustion

Cervical cancer remains the most prevalent gynecological malignant disease. Reprogramming tumor immune metabolism stands out as a novel promising therapeutic target. Here, we identified serine incorporator 2 (SERINC2) as a critical gene which highly expressed in cervical cancer and negatively correlated with clinical outcomes. Through functional assays, SERINC2 was determined to play a pro-tumoral role both

Extracellular vesicles carrying miR-6836 derived from resistant tumor cells transfer cisplatin resistance of epithelial ovarian cancer via DLG2-YAP1 signaling pathway

Low expression of m6A reader YTHDC1 promotes progression of ovarian cancer via PIK3R1/STAT3/GANAB axis

TIE1 promotes cervical cancer progression via Basigin-matrix metalloproteinase axis

Metabolic modulation of CtBP dimeric status impacts the repression of DNA damage repair genes and the platinum sensitivity of ovarian cancer

Platinum drug-based chemotherapy plays a dominant role in OC (ovarian cancer) treatment. The expression of DNA damage repair (DDR) genes is critical in distinguishing drug-sensitive and drug-refractory patients, as well as in the development of drug resistance in long-term treated patients. CtBP is a highly expressed oncogene in OC and was found to repress DDR genes expression in our previous study. In the present study, the formation of CtBP dimers in live cells was studied, and the functional differences between monomeric and oligomeric CtBP were explored by CHIP-seq and RNA-seq. Besides, the dynamics of CtBP dimer formation in response to the metabolic modulation were investigated by the protein fragment complementation (PCA) assays. We show that dimerized CtBP, but not the dimerization-defective mutant, binds to and represses DDR gene expression in OC cells. Treatment of the mice tumors grown from engrafted OC cells by cisplatin disclosed that high-level CtBP expression promotes the CtBP dimerization and increases the therapeutic effect of cisplatin. Moreover, the CtBP dimerization is responsive to the intracellular metabolic status as represented by the free NADH abundance. Metformin was found to increase the dimerization of CtBP and potentiate the therapeutic effect of cisplatin in a CtBP dimerization-dependent manner. Our data suggest that the CtBP dimerization status is a potential biomarker to predict platinum drug sensitivity in patients with ovarian cancer and a target of metformin to improve the therapeutic effect of platinum drugs in OC treatment.

Loss of HRD functional phenotype impedes immunotherapy and can be reversed by HDAC inhibitor in ovarian cancer

In recent years, homologous recombination deficiency (HRD) has not achieved the expected substantial promotion of immunotherapeutic efficacy in ovarian cancer. This study aims to explore the role of HRD functional phenotype as a powerful biomarker in identifying HRD patients who may benefit from immunotherapy. HRD functional phenotype, namely HRD-EXCUTE, was defined as the average level of the 15 hub genes upregulated in HRD ovarian cancer. A decision tree was plotted to evaluate the critical role of HRD-EXCUTE in HRD patients. Agents inducing HRD-EXCUTE were identified by CMAP web (Connectivity Map). The mechanisms and immunotherapeutic effect of PARPi and HDACi in promoting HRD-EXCUTE was examined

The inhibition of YTHDF3/m6A/LRP6 reprograms fatty acid metabolism and suppresses lymph node metastasis in cervical cancer

The lipid synthesis of fatty acid (FA) represents a significant hallmark in the occurrence and progression of malignant tumor, which are associated with lymph node (LN) metastasis. Elucidation of the molecular mechanisms underlying LN metastasis could provide therapeutic strategies for cervical cancer (CCa). N6-Methyladenosine (m

SLC5A3 is important for cervical cancer cell growth

Novel molecular targets for cervical cancer must be identified. This study examined the role of SLC5A3, a myo-inositol transporter, in the pathogenesis of cervical cancer. Through boinformatics analysis, we showed that the

Validation of ESM1 Related to Ovarian Cancer and the Biological Function and Prognostic Significance

Discovery of a novel HDACi structure that inhibits the proliferation of ovarian cancer cells in vivo and in vitro

Histone deacetylases (HDACs) exhibit increased expression in cancer and promote oncogenesis via the acetylation of or interactions with key transcriptional regulators. HDAC inhibitors (HDACis) decrease HDAC activity to selectively inhibit the occurrence and development of tumors. Our study screened and obtained a new HDACi structure.

A new SIRT1 inhibitor, MHY2245, induces autophagy and inhibits energy metabolism via PKM2/mTOR pathway in human ovarian cancer cells

Ovarian cancer is a common gynecological cancer that is found worldwide. Class III histone deacetylase (HDAC) inhibitors, a new class of anticancer agents, induce autophagy in various human cancer cells. The aim of the present study was to investigate the antitumor activity of MHY2245, a new synthetic SIRT inhibitor, on human ovarian cancer cells. We found that MHY2245 exhibited potent cytotoxicity to SKOV3 cells in a time- and concentration-dependent manner. The cytotoxicity of MHY2245 (IC

Lin28A Regulates Stem-like Properties of Ovarian Cancer Cells by Enriching RAN and HSBP1 mRNA and Up-regulating its Protein Expression

Ovarian cancer (OC) is one of the malignant tumors that seriously threaten women's health, with the highest mortality rate in gynecological malignancies. The prognosis of patients with advanced OC is still poor, and the 5-year survival rate is only 20-30%. Therefore, how to improve the early diagnosis rate and therapeutic effect are urgent for patients with OC. In this research, we found that Lin28A can promote the expression of stem cell marker molecules CD133, CD44, OCT4 and Nanog. We later confirmed that Lin28A can enrich the mRNA of ras-related nuclear protein (RAN) and heat shock factor binding protein 1 (HSBP1) through RIP assay, and that Lin28A can regulate their protein expression. We also identified that RAN and HSBP1 are highly expressed in OC tissues, and that they are significantly positively correlated with the expression of Lin28A and negatively correlated with the survival prognosis of OC patients. After stable knockdown of RAN or HSBP1 in OC cells with high expression of Lin28A, the expression of the stem cell marker molecules such as OCT4, CD44 and Nanog are reduced. And after knocking down of RAN or HSBP1 in Lin28A highly expressed OC cells, the survival and invasion of OC cells and tumor size of OC xenograft in nude mice were markedly inhibited and apoptosis was increased. Our data also showed that knock down of RAN or HSBP1 can inhibit the invasion ability of OC cells by decreasing the expression of N-cadherin, Vimentin and promoting the expression of E-cadherin. Meanwhile, knockdown of RAN or HSBP1 induced cell apoptosis by inhibiting the expression of PARP. Our results indicated that Lin28A could regulate the biological behaviors in OC cells through RAN/HSBP1. These findings suggest that Lin28A/RAN/HSBP1 can be used as a marker for diagnosis and prognosis of OC patients, and RAN/HSBP1 may be a potential new target for gene therapy of OC.

Quantitative determination of niraparib and olaparib tumor distribution by mass spectrometry imaging

Up-regulation of MELK by E2F1 promotes the proliferation in cervical cancer cells

Cervical cancer is a common gynecologic cancer and a frequent cause of death. In this study, we investigated the role of MELK (maternal embryonic leucine zipper kinase) in cervical cancer. We found that HPV 18 E6/E7 promoted MELK expression by activating E2F1. MELK knockdown blocked cancer cells growth. Furthermore, we used MELK-8A to inhibit the kinase activity of MELK and caused the G2/M phase arrest of cancer cells. Under the treatment of inhibitors, Hela cells formed multipolar spindles and eventually underwent apoptosis. We also found that MELK is involved in protein translation and folding during cell division through the MELK interactome and the temporal proteomic analysis under inhibition with MELK-8A. Altogether, these results suggest that MELK may play a vital role in cancer cell proliferation and indicate a potential therapeutic target for cervical cancer.

Tandem CAR-T cells targeting FOLR1 and MSLN enhance the antitumor effects in ovarian cancer

Given the heterogeneity of solid tumors, single-target CAR-T cell therapy often leads to recurrence, especially in ovarian cancer (OV). Here, we constructed a Tandem-CAR targeting two antigens with secretory activity (IL-12) to improve the effects of CAR-T cell therapy. Twenty coexpressed upregulated genes were identified from the GEO database, and we found FOLR1 (folate receptor 1) and MSLN (mesothelin) were specifically and highly expressed in cancer tissues and only 11.25% of samples were negative for both antigens. We observed an increased proliferation rate for these three CAR-T cells, and Tandem CAR-T cells could efficiently lyse antigen-positive OV cells

Specific Pyruvate Kinase M2 Inhibitor, Compound 3K, Induces Autophagic Cell Death through Disruption of the Glycolysis Pathway in Ovarian Cancer Cells

Ovarian cancer is a common cause of death among gynecological cancers. Although ovarian cancer initially responds to chemotherapy, frequent recurrence in patients remains a therapeutic challenge. Pyruvate kinase M2 (PKM2) plays a pivotal role in regulating cancer cell survival. However, its therapeutic role remains unclear. Here, we investigated the anticancer effects of compound 3K, a specific PKM2 inhibitor, on the regulation of autophagic and apoptotic pathways in SK-OV-3 (PKM2-overexpressing human ovarian adenocarcinoma cell line). The anticancer effect of compound 3K was examined using MTT and colony formation assays in SK-OV-3 cells. PKM2 expression was positively correlated with the severity of the tumor, and expression of pro-apoptotic proteins increased in SK-OV-3 cells following compound 3K treatment. Compound 3K induced AMPK activation, which was accompanied by mTOR inhibition. Additionally, this compound inhibited glycolysis, resulting in reduced proliferation of SK-OV-3 cells. Compound 3K treatment suppressed tumor progression in an

Free CA125 promotes ovarian cancer cell migration and tumor metastasis by binding Mesothelin to reduce DKK1 expression and activate the SGK3/FOXO3 pathway

The sphingosine kinase inhibitor SKI-V suppresses cervical cancer cell growth

Overexpression and/or overactivation of sphingosine kinase 1/2 (SphK1/2) is important for tumorigenesis and progression of cervical cancer. The current study examined the potential activity and signaling mechanisms of SKI-V, a non-lipid small molecule SphK inhibitor, against cervical cancer cells. In different primary and immortalized cervical cancer cells, SKI-V exerted significant anti-cancer activity by inhibiting cell viability, colony formation, proliferation, cell cycle progression and cell migration. Significant apoptosis activation was detected in SKI-V-treated cervical cancer cells. Significantly, SKI-V also provoked programmed necrosis cascade in cervical cancer cells, as it induced mitochondrial p53-cyclophilin-D-adenine nucleotide translocator-1 (ANT1) complexation, mitochondrial membrane potential collapse, reactive oxygen species production and the release of lactate dehydrogenase into the medium. Further, SKI-V blocked SphK activation and induced ceramide accumulation in primary cervical cancer cells, without affecting SphK1/2 expression. SKI-V-induced cytotoxicity in cervical cancer cells was largely inhibited by sphingosine-1-phosphate or the SphK1 activator K6PC-5, but was sensitized by adding the short-chain ceramide C6. Moreover, SKI-V inhibited Akt-mTOR (mammalian target of rapamycin) activation in primary cervical cancer cells, and its cytotoxicity was mitigated by a constitutively-active Akt.

HPV E6/E7 promotes aerobic glycolysis in cervical cancer by regulating IGF2BP2 to stabilize m6A-MYC expression

Enhanced aerobic glycolysis constitutes an additional source of energy for tumor proliferation and metastasis. Human papillomavirus (HPV) infection is the main cause of cervical cancer (CC); however, the associated molecular mechanisms remain poorly defined, as does the relationship between CC and aerobic glycolysis. To investigate whether HPV 16/18 E6/E7 can enhance aerobic glycolysis in CC, E6/E7 expression was knocked down in SiHa and HeLa cells using small interfering RNA (siRNA). Then, glucose uptake, lactate production, ATP levels, reactive oxygen species (ROS) content, extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) were evaluated. RNA-seq was used to probe the molecular mechanism involved in E6/E7-driven aerobic glycolysis, and identified IGF2BP2 as a target of E6/E7. The regulatory effect of IGF2BP2 was confirmed by qRT-PCR, western blot, and RIP assay. The biological roles and mechanisms underlying how HPV E6/E7 and IGF2BP2 promote CC progression were confirmed

Rab31 promotes the invasion and metastasis of cervical cancer cells by inhibiting MAPK6 degradation

Persistent infection with high-risk human papillomavirus (HPV) is the main risk factor for cervical cancer. Our mass spectrometry data showed that the Ras-associated binding protein Rab31 was upregulated by HPV; however, little is known regarding the role of Rab31 in the metastasis of cervical cancer cells. In this study, we showed that Rab31 was highly expressed in cervical cancer tissues and cells, and both HPV E6 and E7 promoted the expression of Rab31. Rab31 knockdown inhibited while Rab31 overexpression promoted the migration and invasion capabilities of cervical cancer cells. Additionally, Rab31 knockdown inhibited the epithelial-mesenchymal transition (EMT) and cytoskeletal rearrangement in cervical cancer cells. Furthermore, Rab31 interacted with mitogen-activated protein kinase 6 (MAPK6), and Rab31 knockdown inhibited the expression of MAPK6, which was mainly localized in the cytoplasm. More importantly, Rab31 knockdown promoted and Rab31 overexpression inhibited MAPK6 degradation. Accordingly, MAPK6 overexpression restored the decreased migration potential caused by Rab31 knockdown. Finally, a xenograft mouse model showed that Rab31 knockdown in cervical cancer cells led to reduced tumor growth and impaired lung and liver metastasis

Triptonide-mediated PTGS2 Inhibition Induces Autophagic Cell Death to Suppress the Progression of Triple-negative Breast Cancer and Epithelial Ovarian Cancer

Overcoming Ferroptosis-Induced Exhaustion of NK Cells through Inhibition of the ATF3-Mediated Integrated Stress Response in Ovarian Cancer

The absence of cytotoxic effector cells, such as CD8⁺ T cells or Natural Killer (NK) cells, within tumors establishes an immune-cold tumor microenvironment (TME), contributing to poor immunotherapy responses, as observed in ovarian cancer. Although prior studies implicate NK cell exhaustion within the TME related to ferroptosis, the underlying mechanisms remain undefined. This study demonstrates that upon infiltrating the ovarian cancer TME, NK cells activate an integrated stress response (ISR) centered on ATF3. This ATF3-mediated ISR suppresses NRF2 expression, compromising their ability to counteract oxidative stress and ultimately triggering ferroptosis. Critically, we show that co-treatment with the ISR inhibitor ISRIB and NK cells not only prevents NK cell ferroptosis but also synergizes to enhance tumor cell killing. These findings provide novel insights into the mechanisms driving NK cell exhaustion within the TME and identify ISR inhibition as a promising therapeutic target and intervention strategy for developing NK cell-based therapies against ovarian cancer.

PSMC6 regulation of ovarian cancer cisplatin resistance unravels a new mode for proteasome targeting

Ovarian carcinoma has still a poor prognosis. CRISPR/Cas9 loss-of-function screen revealed a relationship between the PSMC6 proteasome subunit expression and survival of cisplatin-sensitive and -resistant ovarian carcinoma cells. Increased levels of PSMC6 were evidenced in multiple ovarian carcinoma cell lines versus normal cells. An association between PSMC6 levels and tumour stages as well as with a reduced progression-free survival was found. Since a PSMC6 interactome analysis evidenced limited knowledge on PSMC6 biology, mechanistic studies were carried out. PSMC6 knockdown indicated reduced cell growth and clonogenicity in cisplatin-sensitive IGROV-1 and -resistant IGROV-1/Pt1 cells, with a higher impact in resistant cells. This behaviour was accompanied by the accumulation of ubiquitinated proteins and down-regulation of ERK1/2 phosphorylation mediated by increased DUSP6. PSMC6 silencing increased sensitivity to cisplatin in IGROV-1/Pt1 cells as shown by clonogenic assay and 3D spheroids. Since PSMC6 knockdown did not change sensitivity to 20S and 19S proteasome inhibitors, we suggest a new mode of proteasome targeting by interference with a proteasome ATPase. Overall, a link between PSMC6 and ovarian carcinoma aggressiveness is envisioned, highlighting PSMC6 as a potential diagnostic and therapeutic target.

Deubiquitinases in Ovarian Cancer: Role in Drug Resistance and Tumor Aggressiveness

Ovarian cancer is a lethal disease due to late diagnosis and occurrence of drug resistance that limits the efficacy of platinum-based therapy. Drug resistance mechanisms include both tumor intrinsic and tumor microenvironment-related factors. A role for deubiquitinases (DUBs) is starting to emerge in ovarian cancer. DUBs are a large family of enzymes that remove ubiquitin from target proteins and participate in processes affecting drug resistance such as DNA damage repair and apoptosis. Besides, DUBs modulate the functions of T cell populations favoring an immune suppressed microenvironment. Three DUBs are proteasome-associated, whereas the large majority are not. Among the former DUBs, USP14 has been proposed to modulate transcription factors such as Bcl6 and BACH1. In addition, RPN11/PSMD14 interferes with various processes including epithelial mesenchymal transition, also favored by non-proteasomal DUBs such as USP1 by acting on Snail. Besides, USP8 by stabilizing HER family receptors can confer drug resistance. Overall, DUBs appear to be druggable, with several inhibitors under development. Based on DUBs biological role, DUBs targeting appears promising in view of combination strategies involving different therapeutic approaches. Here, we summarize the relevance of DUBs in ovarian carcinoma and provide insights into future challenges for the treatment of this disease.

Olaparib combined with CDK12-IN-3 to promote genomic instability and cell death in ovarian cancer

Large-scale phase III clinical trials of Olaparib have revealed benefits for ovarian cancer patients with BRCA gene mutations or homologous recombination deficiency (HRD). However, fewer than 50% of ovarian cancer patients have both BRCA mutations and HRD. Therefore, improving the effect of Olaparib in HR-proficient patients is of great clinical value. Here, a combination strategy comprising Olaparib and CDK12-IN-3 effectively inhibited the growth of HR-proficient ovarian cancer in cell line, patient-derived organoid (PDO), and mouse xenograft models. Furthermore, the combination strategy induced severe DNA double-strand break (DSB) formation, increased NHEJ activity in the G2 phase, and reduced HR activity in cancer cells. Mechanistically, the combination treatment impaired Ku80 poly(ADP-ribosyl)ation (PARylation) and phosphorylation, resulting in PARP1-Ku80 complex dissociation. After dissociation, Ku80 occupancy at DSBs and the resulting Ku80-primed NHEJ activity were increased. Owing to Ku80-mediated DNA end protection, MRE11 and Rad51 foci formation was inhibited after the combination treatment, suggesting that this treatment suppressed HR activity. Intriguingly, the combination strategy expedited cGAS nuclear relocalization, further suppressing HR and, conversely, increasing genomic instability. Moreover, the inhibitory effect on cell survival persisted after drug withdrawal. These findings provide a rationale for the clinical application of CDK12-IN-3 in combination with Olaparib.

Paris saponin VII reverses resistance to PARP inhibitors by regulating ovarian cancer tumor angiogenesis and glycolysis through the RORα/ECM1/VEGFR2 signaling axis

The emergence of Poly (ADP-ribose) polymerase inhibitors (PARPi) has marked the beginning of a precise targeted therapy era for ovarian cancer. However, an increasing number of patients are experiencing primary or acquired resistance to PARPi, severely limiting its clinical application. Deciphering the underlying mechanisms of PARPi resistance and discovering new therapeutic targets is an urgent and critical issue to address. In this study, we observed a close correlation between glycolysis, tumor angiogenesis, and PARPi resistance in ovarian cancer. Furthermore, we discovered that the natural compound Paris saponin VII (PS VII) partially reversed PARPi resistance in ovarian cancer and demonstrated synergistic therapeutic effects when combined with PARPi. Additionally, we found that PS VII potentially hindered glycolysis and angiogenesis in PARPi-resistant ovarian cancer cells by binding and stabilizing the expression of RORα, thus further inhibiting ECM1 and interfering with the VEGFR2/FAK/AKT/GSK3β signaling pathway. Our research provides new targeted treatment for clinical ovarian cancer therapy and brings new hope to patients with PARPi-resistant ovarian cancer, effectively expanding the application of PARPi in clinical treatment.

Selectively targeting BCL6 using a small molecule inhibitor is a potential therapeutic strategy for ovarian cancer

Ovarian cancer is one of the tumors with the highest fatality rate among gynecological tumors. The current 5-year survival rate of ovarian cancer is <35%. Therefore, more novel alternative strategies and drugs are needed to treat ovarian cancer. The transcription factor B-cell lymphoma 6 (BCL6) is critically associated with poor prognosis and cisplatin resistance in ovarian cancer treatment. Therefore, BCL6 may be an attractive therapeutic target for ovarian cancer. However, the role of targeting BCL6 in ovarian cancer remains elusive. Here, we developed a novel BCL6 small molecule inhibitor, WK369, which exhibits excellent anti-ovarian cancer bioactivity, induces cell cycle arrest and causes apoptosis. WK369 effectively inhibits the growth and metastasis of ovarian cancer without obvious toxicity

GRP75-faciliated Mitochondria-associated ER Membrane (MAM) Integrity controls Cisplatin-resistance in Ovarian Cancer Patients

LncRNA CASC15, MiR-23b Cluster and SMAD3 form a Novel Positive Feedback Loop to promote Epithelial-Mesenchymal Transition and Metastasis in Ovarian Cancer

Cancer Susceptibility Candidate 15 (CASC15), which is a newly identified long noncoding RNA crucial for epigenetic regulation in human tumors, was found to be associated with poor prognosis of the patients with ovarian cancer by utilizing The Cancer Genome Atlas and Gene Expression Omnibus database. Therefore, the purpose of this paper was to explore the functional role and latent molecular mechanism of CASC15 in the progression of ovarian cancer.

Identification of Gαi3 as a novel molecular therapeutic target of cervical cancer

Here we studied expression and potential functions of Gαi3 in cervical cancer. The bioinformatics analysis together with the results from local patients' tissues revealed that Gαi3 expression was remarkably elevated in human cervical cancer tissues and different cervical cancer cells, and was associated with poor overall survival and poor disease-specific survival of patients. Gαi3 depletion resulted in profound anti-cervical cancer activity. In primary or immortalized cervical cancer cells, Gαi3 shRNA or CRISPR/Cas9-caused Gαi3 knockout/KO largely hindered cell proliferation and migration, and provoked apoptosis. On the contrast, ectopic Gαi3 overexpression further enhanced cervical cancer proliferation and migration. Akt-mTOR activation in primary cervical cancer cells was significantly reduced after Gαi3 silencing or KO, but was augmented following Gαi3 overexpression. Further studies revealed that the transcription factor GATA4 binding to Gαi3 promoter region was significantly enhanced in cervical cancer tissues and cells. Gαi3 expression was decreased by GATA4 shRNA, but upregulated following GATA4 overexpression.