Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

ADARB1 inhibits glycolysis and progression of cervical cancer through the HMGB1/PFKFB3 axis

Cervical cancer (CC) remains one of the most prevalent gynecological malignancies worldwide, with patients diagnosed at advanced stages often facing poor prognoses due to the lack of effective therapeutic options. ADARB1 (Adenosine Deaminase Acting on RNA 1), an RNA-editing enzyme, has been implicated in the pathogenesis of various cancers; however, its functional role in cervical cancer remains largely unexplored. In this study, we observed a significant downregulation of ADARB1 expression in both cervical cancer tissues and cell lines, which was associated with unfavorable clinical outcomes. Functional assays revealed that ADARB1 overexpression markedly inhibited the proliferation, migration, invasion, and glycolytic activity of cervical cancer cells, whereas ADARB1 knockdown exerted the opposite effects. Mechanistically, we found that ADARB1 mRNA binds to HMGB1 (High Mobility Group Box 1) protein and regulates its expression via the ubiquitin-proteasome pathway, thereby modulating the malignant phenotype of cervical cancer. Notably, ectopic expression of HMGB1 partially reversed the suppressive effects of ADARB1 on cell proliferation and glycolysis. Further investigation revealed that HMGB1 interacts with PFKFB3 (6-Phosphofructo-2-Kinase/Fructose-2,6-Bisphosphatase 3), a key regulatory enzyme in glycolysis, and modulates its protein stability, suggesting the presence of a critical HMGB1/PFKFB3 signaling axis in cancer metabolism. ADARB1 exerts its anti-tumor effects primarily through the HMGB1/PFKFB3 pathway. Collectively, these findings identify ADARB1 as a novel tumor suppressor in cervical cancer and a promising therapeutic target for clinical intervention.

ClC-3 inhibition induces autophagy to reverse cisplatin resistance in cervical cancer via the Akt/mTOR pathway

Cervical cancer is one of the most prevalent types of cancer among women. Nowadays, surgery is still the primary treatment for cervical cancer. Cisplatin was regarded as the standard medication for non-surgical therapy. Unfortunately, some patients respond poorly to cisplatin, resulting in a significantly reduced survival rate. Our earlier study revealed that chloride channel-3 (ClC-3) is highly expressed in cervical cancer and other researchers revealed a tight relationship between ClC-3 and autophagy-induced chemoresistance in different tumor types. Consequently, the purpose of this article is to figure out the link between ClC-3-related autophagy and cisplatin sensitivity in cervical cancer. We discovered that inhibiting ClC-3 expression could enhance the sensitivity of cervical cancer cell line (SiHa) to cisplatin and even reverse the cisplatin resistance in a cisplatin-resistant cervical cancer cell line (SiHa/DDP). This process was initiated by the cell autophagy which the Akt-mTOR pathway mediated. A ClC-3 specific inhibitor (Chlorotoxin TFA, CLTX) made cervical cancer xenograft implantation more sensitive to cisplatin in vivo. All these findings revealed the mechanism and connection between ClC-3 and cisplatin sensitivity in cervical cancer, as well as provided new light into the application of the ClC-3 specific inhibitor for cisplatin sensitization in cervical cancer.

Vimentin-targeting adaptogen withaferin A: Potential to selectively suppress cervical cancer – Single-cell microspectroscopic and molecular analysis

This study investigates the preferential anticancer effects of withaferin A, an adaptogenic compound, on primary and metastatic cervical cancer cells (C-33 A and CaSki, respectively) and non-cancerous skin fibroblast cells (Detroit-551). Employing a multi-modal approach, we combined biological assays with advanced vibrational spectroscopic imaging techniques, including Fourier-transform infrared (FT-IR), Raman (RS), and atomic force microscopy (AFM). The results revealed a dose-dependent reduction in cell viability, with a more pronounced effect observed in C-33 A cells compared to CaSki and fibroblasts, indicating a heightened sensitivity of C-33 A cells to withaferin A. The comet assay revealed significantly higher levels of DNA damage in primary tumor C-33A cells, whereas minimal DNA breaks were observed in fibroblasts and metastatic cells, further confirming the higher sensitivity of cancer cells compared to fibroblasts. Fluorescence staining and AFM topography imaging showed morphological alterations in cancer cells at higher withaferin A doses and longer incubation times. Flow cytometry analysis revealed significant apoptotic changes in primary C-33A cells due to withaferin A treatment, highlighting a large amount of cells undergoing late apoptosis, compared to a weaker apoptotic effect on metastatic CaSki cells and negligible effect for fibroblasts. Spectroscopic analyses revealed molecular alterations in lipid, protein, and nucleic acid composition, indicative of withaferin A's impact on cellular membranes and genetic material. These findings highlight withaferin A as a promising therapeutic agent with the potential to preferentially target primary cervical cancer cells, while minimizing toxicity to healthy cells.

Deep multi-omics integration approach reveals new molecular features of uterine leiomyosarcoma

Uterine leiomyosarcoma (uLMS) is a rare and aggressive cancer representing approximately 25 % of all uterine malignancies. The molecular heterogeneity and pathogenesis of uLMS are not well understood, and translational studies aimed at discovering the vulnerabilities of this tumor type are of high priority. We conducted an innovative comprehensive multi-omics integration study from DNA to protein using freshly frozen tumors. Here, we show that two tumors harbor actionable therapeutic targets, IDH1_p.Arg132Cys and KRAS_p.Gly12Cys, and homologous recombination deficiency (HRD) is the most predominant genomic signature. Additionally, 80 % of the samples presented a chromothripsis signature, reinforcing the aneuploidy phenotype of these tumors. Tumors with a high proliferation score and high Ki67 expression was associated with worse overall survival (OS). We observed a high frequency of balanced fusion events involving EEF1A1 with enrichment of the EGFR pathway. For the first time, uLMS proteomics analysis showed the enrichment of pathways associated with suppression of the innate immune system and ECM organization. Finally, our comprehensive multi-omics integration analysis identified amplification of the CTHRC1 gene from the matrisome, with a negative impact on OS. Interestingly, the expression of Ki67 and CTHRC1 exhibits a strong negative correlation, underscoring two distinct and mutually exclusive biological profiles in uLMS: (i) highly proliferative tumors, characterized by elevated Ki67 expression, and (ii) tumors driven by ECM remodeling, marked by high CTHRC1 levels. Taken together, this deep functional multi-omics approach contributes to the detection of new molecular features of uLMS and suggests that patients could benefit from precision oncology in clinical practice.

SLFN11 and ATR as targets for overcoming cisplatin resistance in ovarian cancer cells

The levels and activities of the DNA/RNA helicase schlafen11 (SLFN11) and the serine/threonine-protein kinase ataxia telangiectasia and Rad3-related protein (ATR) may determine cancer cell sensitivity to DNA damaging agents, including platinum drugs. Here, we studied the roles of SLFN11 and ATR in cisplatin resistance of ovarian cancer using cell lines displaying acquired or intrinsic cisplatin resistance. W1CR, the cisplatin-resistant subline of W1 ovarian cancer cells, displayed reduced SLFN11 levels. HDAC inhibition using entinostat returned an epigenetic downregulation of SLFN11 in W1CR cells, caused SLFN11 re-expression and re-sensitized these cells to cisplatin. Moreover, entinostat also sensitized intrinsically resistant EFO21 ovarian cancer cells to cisplatin by upregulating SLFN11. However, SLFN11 was not involved in cisplatin resistance in all other cell models. Thus, SLFN11 expression is not a general cisplatin resistance marker in ovarian cancer. In contrast, inhibition of the DNA damage repair master regulator ATR using sub-toxic concentrations of elimusertib sensitized parental cell lines as well as intrinsically resistant EFO21 cells to cisplatin, and fully reversed acquired cisplatin resistance in cisplatin-adapted sublines W1CR, A2780cis, and Kuramochi

Lysine lactylation-based insight to understanding the characterization of cervical cancer

Lysine lactylation (Kla), a recently discovered post-translational modification (PTM), is not only present in histone proteins but also widely distributed among non-histone proteins in tumor cells and immunocytes. However, the precise characterization and functional implications of these non-histone Kla proteins remain to be explored. Herein, a comprehensive proteomic analysis of Kla was conducted in HeLa cells. As a result, a total of 3633 Kla sites on 1637 proteins were identified. Subsequently, the stable Kla substrates were obtained and sorted to investigate the characterization and function of Kla proteins. Moreover, we characterized the Kla-related features of cervical cancers through integrative analyses of multiple datasets with proteomes, transcriptomes and single-cell transcriptome profiling. Kla-related genes (KRGs) were used to stratify cervical cancers into two clusters (C1 and C2). C2 cluster display inhibition in glycosylation and increased oxidative phosphorylation activity with high survival rate. In addition, we constructed a prognostic model based on two lactate signature genes, namely ISY1 and PPP1R14B. Interestingly, our findings revealed a negative correlation between PPP1R14B expression and the infiltration of CD8

MTH1 inhibition synergizes with ROS-inducing agents to trigger cervical cancer cells undergoing parthanatos

Cervical cancer cells possess high levels of reactive oxygen species (ROS); thus, increasing oxidative stress above the toxicity threshold to induce cell death is a promising chemotherapeutic strategy. However, the underlying mechanisms of cell death are elusive, and efficacy and toxicity issues remain. Within DNA, 8-oxo-7,8-dihydroguanine (8-oxoG) is the most frequent base lesion repaired by 8-oxoguanine glycosylase 1 (OGG1)-initiated base excision repair. Cancer cells also express high levels of MutT homolog 1 (MTH1), which prevents DNA replication-induced incorporation of 8-oxoG into the genome by hydrolyzing 8-oxo-7,8-dihydro-2'-deoxyguanosine 5'-triphosphate (8-oxo-dGTP). Here, we revealed that ROS-inducing agents triggered cervical cancer to undergo parthanatos, which was mainly induced by massive DNA strand breaks resulting from overwhelming 8-oxoG excision by OGG1. Furthermore, the MTH1 inhibitor synergized with a relatively low dose of ROS-inducing agents by enhancing 8-oxoG loading in the DNA. In vivo, this drug combination suppressed the growth of tumor xenografts, and this inhibitory effect was significantly decreased in the absence of OGG1. Hence, the present study highlights the roles of base repair enzymes in cell death induction and suggests that the combination of lower doses of ROS-inducing agents with MTH1 inhibitors may be a more selective and safer strategy for cervical cancer chemotherapy.

Regulation of self-renewal in ovarian cancer stem cells by fructose via chaperone-mediated autophagy

The chaperone-mediated autophagy (CMA) pathway is deregulated in different types of cancers; however, its role in cancer stem cells (CSCs) is unknown yet. Development of ovarian cancer, the most lethal gynecological type of cancer, involves the metastasis of CSCs to the abdominal cavity. This study aims to determine the role of CMA in ovarian CSCs. We found that the transcription factor EB (TFEB) and trehalose, a disaccharide that induces TFEB activation, enhance the expression of octamer-binding transcription factor 4 (OCT4) stem cell and lysosomal-associated membrane protein 2A (LAMP2A) CMA markers. However, trehalose did not increase the level of the LC3II macroautophagy marker in ovarian CSCs. In A2780 and SKOV3 ovarian CSCs, LAMP2A and heat shock protein 70 (HSC70) exhibited higher expression levels than in normal adherent cells. Our results showed that the silencing of the LAMP2A gene resulted in reduced sphere formation and enhanced GLUT5 expression in ovarian CSCs. Moreover, the treatment with fructose reduced sphere formation and enhanced the expression levels of LAMP2A, SOX2, and OCT4 in ovarian CSCs. The KEGG functional analysis revealed that differentially expressed genes were enriched in the ferroptosis pathway in A2780-spheroid (SP) cells after treatment with fructose. In A2780-SP and SKOV3-SP cells, the level of SLC7A11 decreased whereas FTH increased after treatment with fructose. Taken together, our results suggest that CMA is mediated in CSCs via fructose metabolism.

OTUD1 enhances gastric cancer aggressiveness by deubiquitinating EBV-encoded protein BALF1 to stabilize the apoptosis inhibitor Bcl-2

Physical interaction between STAT3 and AP1 in cervical carcinogenesis: Implications in HPV transcription control

The constitutive activation and aberrant expression of Signal Transducer and Activator of Transcription 3 (STAT3) plays a key role in initiation and progression of cervical cancer (CaCx). How STAT3 influences HPV transcription is poorly defined. In the present study, we probed direct and indirect interactions of STAT3 with HPV16/18 LCR. In silico assessment of cis-elements present on LCR revealed the presence of potential STAT3 binding motifs. However, experimental validation by ChIP-PCR could not confirm any specific STAT3 binding on HPV16 LCR. Protein-protein interaction (PPI) network analysis of STAT3 with other host transcription factors that bind LCR, highlighted the physical association of STAT3 with c-FOS and c-JUN. This was further confirmed in vitro by co-immunoprecipitation, where STAT3 co-immunoprecipitated with c-FOS and c-JUN in CaCx cells. The result was supported by immunocytochemical analysis and colocalization of STAT3 with c-FOS and c-JUN. Positive signals in proximity ligation assay validated physical interaction and colocalization of STAT3 with AP1. Colocalization of STAT3 with c-FOS and c-JUN increased upon IL-6 treatment and decreased post-Stattic treatment. Alteration of STAT3 expression affected the subcellular localization of c-FOS and c-JUN, along with the expression of viral oncoproteins (E6 and E7) in CaCx cells. High expression of c-JUN in tumor tissues correlated with poor prognosis in both HPV16 and HPV18 CaCx cohort whereas high expression of STAT3 correlated with poor prognosis in HPV18 CaCx lesions only. Overall, the data suggest an indirect interaction of STAT3 with HPV LCR via c-FOS and c-JUN and potentiate transcription of viral oncoproteins.

IGF1R-α6 integrin-S100A4 network governs the organ-specific metastasis of chemoresistant epithelial ovarian cancer cells

Recurrent metastatic epithelial ovarian cancer (EOC) is challenging and associated with treatment limitations, as the mechanisms governing the metastatic behavior of chemoresistant EOC cells remain elusive. Using orthotopic xenograft mouse models of sensitive and acquired platinum-taxol-resistant A2780 EOC cells, we studied the mechanistic role of insulin like growth factor 1 receptor (IGF1R) signaling in the regulation of organ-specific metastasis of EOC cells undergoing acquirement of chemoresistance. Biochemical assays and organ-specific fibroblast-EOC cell co-culture were used to study the differential metastatic characteristics of sensitive vs. chemoresistant EOC cells, and the key molecule/s underlying the organ-specific homing of chemoresistant EOC cells were identified through subtractive LC/MS profiling of the co-culture secretome. The role of the identified molecule was validated through genetic/pharmacologic perturbation experiments. Acquired chemoresistance augmented organ-specific metastasis of EOC cells and enhanced lung homing, particularly for the late-stage chemoresistant cells, which was abrogated after IGF1R silencing. Escalation of chemoresistance (intrinsic and acquired) conferred EOC cells with higher adhesion toward primary lung fibroblasts, largely governed by the α6 integrin-IGF1R dual signaling axes. Subtractive analysis of the co-culture secretome revealed that interaction with lung fibroblasts induced the secretion of S100A4 from highly resistant EOC cells, which reciprocally activated lung fibroblasts. Genetic and pharmacologic inhibition of S100A4 significantly lowered distant metastases and completely abrogated lung-tropic nature of late-stage chemoresistant EOC cells. These results indicate that chemoresistance exacerbates organ-specific metastasis of EOC cells via the IGF1R-α6 integrin-S100A4 molecular network, of which S100A4 may serve as a potential target for the treatment of recurrent metastatic EOC.

Decoding molecular interplay between RUNX1 and FOXO3a underlying the pulsatile IGF1R expression during acquirement of chemoresistance

Hyperactive Insulin like growth factor-1-receptor (IGF1R) signalling is associated with development of therapy resistance in many cancers. We recently reported a pulsatile nature of IGF1R during acquirement of platinum-taxol resistance in Epithelial Ovarian Cancer (EOC) cells and a therapy induced upregulation in IGF1R expression in tumors of a small cohort of high grade serous EOC patients. Here, we report Runt-related transcription factor 1 (RUNX1) as a novel transcriptional regulator which along with another known regulator Forkhead Box O3 (FOXO3a), drives the dynamic modulation of IGF1R expression during platinum-taxol resistance development in EOC cells. RUNX1-FOXO3a cooperatively bind to IGF1R promoter and produce a transcriptional surge during onset of resistance and such co-operativity falls apart when cells attain maximal resistance resulting in decreased IGF1R expression. The intriguing descending trend in IGF1R and FOXO3a expressions is caused by a Protein Kinase B (AKT)-FOXO3a negative feedback loop exclusively present in the highly resistant cells eliciting the pulsatile behaviour of IGF1R and FOXO3a. In vivo molecular imaging revealed that RUNX1 inhibition causes significant attenuation of the IGF1R promoter activity, decreased tumorigenicity and enhanced drug sensitivity of tumors of early resistant cells. Altogether our findings delineate a dynamic interplay between several molecular regulators driving pulsatile IGF1R expression and identify a new avenue for targeting EOC through RUNX1-IGF1R axis during acquirement of chemoresistance.

Molecular mechanisms restoring olaparib efficacy through ATR/CHK1 pathway inhibition in olaparib-resistant BRCA1/2MUT ovarian cancer models

Resistance to olaparib inevitably develops in ovarian cancer (OC) patients, highlighting the necessity for effective strategies to improve its efficacy. Here, we established a novel olaparib-resistant patient-derived xenograft model of high-grade serous OC with BRCA1/2 mutations and examined the molecular characteristics of acquired resistance and resensitization to olaparib in treatment-naïve tumors in vivo. Olaparib-resistant xenografts were treated with olaparib, ATR inhibitor (ATRi, ceralasertib), CHK1 inhibitor (CHK1i, MK-8776) or their combinations. Proliferation, apoptosis, ATR/CHK1 activity, PARP signaling, DNA damage response (DDR), epithelial-to-mesenchymal transition (EMT), and MDR1 expression, were examined via RT-qPCR, western blot, and immunohistochemistry. Resistant tumors exhibited defects in PARP and ATR/CHK1 signaling, accompanied by altered expression of proteins involved in DDR and EMT. Olaparib rechallenge combined with ATR/CHK1 inhibitors showed promising synergistic effects on tumor growth inhibition. Mechanistically, combined treatments suppressed tumor proliferation without increasing apoptosis or necrosis, while inducing tumor cell vacuolization indicative of cell death. ATRi combined with olaparib induced or augmented downregulation of ATR, CHK1, PARP1, PARG, BRCA1, γH2AX, and PARylated protein expression, while reversing olaparib-induced upregulation of vimentin, BRCA2, and 53BP1. Our collective findings indicate that ATR/CHK1 pathway inhibition restores the olaparib efficacy in resistant BRCA1/2

Deubiquitylase PSMD14 inhibits autophagy to promote ovarian cancer progression via stabilization of LRPPRC

Autophagy is a key cellular process, which exists in many tumors and plays dual roles in tumor promotion and suppression. However, the role and mechanism of aberrant autophagy in ovarian cancer remains unclear. Ubiquitin-proteasome pathway is the most important pathway for specific protein degradation. Deubiquitinases (DUBs) have crucial roles in all the stages of tumorigenesis and progression. Herein, we explore the DUBs which contribute to aberrant autophagy in ovarian cancer. TCGA data analysis shows that the autophagy level is suppressed, and the selective autophagy receptor SQSTM1/p62 is abnormally high expressed in ovarian cancer. We screen and identify that the deubiquitinase PSMD14 negatively regulates autophagy level. Functional studies show that increased PSMD14 expression remarkably enhances ovarian cancer cells malignancy, whereas knockdown of PSMD14 has the opposite effect. Furthermore, in vivo assays show that knockdown of PSMD14 inhibits the growth, lung and abdominal metastasis of ovarian cancer. Mechanistically, PSMD14 directly interacts with LRPPRC and inhibits its ubiquitination, thereby inhibiting autophagy through LRPPRC/Beclin1-Bcl-2/SQSTM1 signaling pathway. Next, we demonstrate that PSMD14 is upregulated in ovarian cancer and high expression of PSMD14 positively correlates with LRPPRC. Taken together, we clarify the role of autophagy in regulating the ovarian cancer phenotype and provide insights into regulatory mechanism of autophagy in ovarian cancer.

Adaptogenic activity of withaferin A on human cervical carcinoma cells using high-definition vibrational spectroscopic imaging

Despite invaluable advances in cervical cancer therapy, treatment regimens for recurrent or persistent cancers and low-toxicity alternative treatment options are scarce. In recent years, substances classified as adaptogens have been identified as promising drug sources for preventing and treating cancer-based diseases on their ability to attack multiple molecular targets. This paper establishes the effectiveness of inhibition of the neoplastic process by a withaferin A (WFA), an adaptogenic substance, based on an in vitro model of cervical cancer. This study explores for the first time the potential of high-definition vibrational spectroscopy methods, i.e. Fourier-transform infrared (FT-IR) and Raman spectroscopic (RS) imaging at the single-cell level to evaluate the efficacy of the adaptogenic drug. HeLa cervical cancer cells were incubated with various concentrations of WFA at different incubation times. The multimodal spectroscopic approach combined with partial least squares (PLS) regression allowed the identification of molecular changes (e.g., lipids, protein secondary structures, or nucleic acids) induced by WFA at the cellular level. The results clearly illustrate the enormous potential of WFA in inhibiting the proliferation of cervical cancer cells. WFA inhibited the growth of the studied cancer cell line in a dose-dependent manner. Such studies provide comprehensive information on the sensitivity of cells to adaptogenic drugs. This is a fundamental step towards determining the rate and nature of adaptogen-induced changes in cancer cells.

SREBP1a induced PINK1-Parkin mediated mitophagy facilitates ovarian cancer progression

Sterol regulatory element binding protein 1 (SREBP1) has emerged as a central regulator of lipid metabolism, playing a pivotal role in cancer progression. However, the oncogenic potential of SREBP1a is still underexplored. This study investigates the multifaceted contributions of SREBP1a on tumorigenesis, with a particular focus on ovarian cancer. Elevated expression of the SREBP1a isoform was found to enhance proliferation, migration, and invasion of ovarian cancer cells. Mechanistically, SREBP1a induces mitochondrial fission by upregulating DRP1 expression and promoting its activation through ser616 phosphorylation, resulting in a fragmented mitochondrial network that supports enhanced bioenergetic flexibility. In parallel, SREBP1a drives PINK1-Parkin-mediated mitophagy. This coupling of mitochondrial fission and mitophagy possibly ensures mitochondrial quality control, enhances cellular bioenergetics, and increases ATP production, supporting rapid cell proliferation and migration. Experimental evidences reveal that SREBP1 directly regulates DRP1 and PINK1 transcription, reinforcing its role in regulating mitochondrial dynamics. Furthermore, targeting SREBP1 using Fatostatin, a small-molecule inhibitor, effectively disrupts mitochondrial fission, impairs mitophagy, and attenuates tumor progression. These findings highlight the novel role of SREBP1a as a key regulator of mitochondrial dynamics, establishing it as a promising therapeutic target in ovarian cancer. Future studies should explore combinatorial strategies integrating SREBP1a inhibition with existing therapies to improve treatment outcomes.

Pharmacologic interventions targeting ovarian aging, cancer, and mitochondrial dysfunction: An updated evidence

Ovarian aging is a major determinant of female reproductive longevity, characterized by declining oocyte quality and reduced ovarian reserve. With more women delaying childbearing, age-related infertility has become an urgent biomedical concern. Mitochondrial dysfunction plays a central role in this process, leading to oxidative damage and metabolic disturbances that impair oocyte competence. These alterations are linked to poorer outcomes in assisted reproductive technology (ART), particularly for women over 35, who face significantly reduced success rates. This review examines the key mechanisms of ovarian aging, including oxidative stress, DNA damage, telomere shortening, and mitochondrial dysfunction, all contributing to diminished oocyte quality and quantity. Special focus is given to sirtuins, especially SIRT1 and SIRT3, as critical regulators of redox balance in oocytes and granulosa cells. The review also addresses the impact of age-related changes on chromosomal cohesion and ovarian fibrosis. Importantly, mitochondrial insufficiency is increasingly recognized as a factor in broader age-related diseases, such as metabolic disorders and cancer, suggesting shared molecular pathways between reproductive aging and systemic health. Recent advances highlight the potential of targeted nutrient supplementation to modulate redox homeostasis, enhance sirtuin activity, and preserve mitochondrial function-strategies that may benefit both ovarian health and overall aging. This intersection of reproductive biology and mitochondrial medicine is driving interest in pharmacologic interventions to improve oocyte quality and mitigate age-related comorbidities.

Anticancer and chemo-sensitizing effects of annonacin via p53-mediated DNA damage in ovarian cancer

Ovarian cancer (OC) is a highly lethal malignancy in women, often diagnosed at advanced stages. Carboplatin is the primary chemotherapy drug used clinically; however, most patients experience relapse and develop drug resistance after initial treatment, underscoring the urgent need for novel therapeutic strategies. This study investigated the anti-cancer activity and chemo-sensitizing effects of annonacin, an active compound in the fruit extract of Asimina triloba, as well as its underlying mechanisms in OC. Our results demonstrated that annonacin significantly inhibited OC cell viability, DNA replication, and proliferation, while inducing cell cycle arrest and senescence. Additionally, annonacin reduced OC cell-matrix adhesion and suppressed cell migration and invasion. Furthermore, annonacin enhanced the anti-OC efficacy of carboplatin by inducing substantial DNA damage, exhibiting a synergistic anticancer effect. Mechanistically, annonacin exerted potent anti-cancer and anti-migration activities through the p53 signaling pathway-mediated DNA damage response. When combined with carboplatin, this effect was further amplified. In vivo studies showed that annonacin effectively inhibited tumor growth in mice, and its combination with carboplatin demonstrated superior tumor-suppressive capabilities. Acute toxicity assays confirmed that annonacin possesses good biological safety in vivo. Collectively, these findings suggest that annonacin is a promising chemotherapeutic agent for OC treatment and highlight the potential of its combination with carboplatin to improve therapeutic outcomes in OC.

GDF15 drives de novo lipogenesis and contributes to ovarian cancer metastasis

Ovarian cancer is frequently diagnosed at an advanced stage, characterized by extensive metastasis. Recent studies indicate that metastatic and primary tumors exhibit similar mutational landscape, suggesting that non-mutational factors significantly contribute to the metastatic process. Enhanced lipid metabolism has been implicated across various stages of cancer progression, making the targeting of metabolic vulnerabilities a promising therapeutic strategy. In this study, we demonstrate that growth differentiation factor 15 (GDF15), a member of the TGF-β superfamily, which has been Indicated to be associated with several metabolic diseases, is significantly elevated in the serum of ovarian cancer patients, particularly in metastatic lesions compared to primary tumors. Elevated GDF15 levels correlate with reduced overall survival and progression-free survival. Furthermore, we found that GDF15 facilitates tumor metastasis by regulating de novo lipogenesis through the PI3K/AKT signaling pathway. These findings suggest that targeting GDF15-mediated lipid metabolism could provide a novel therapeutic approach to inhibit ovarian cancer metastasis.

Non-coding RNA RMRP governs RAB31-dependent MMP secretion, enhancing ovarian cancer invasion

Non-coding RNAs (ncRNAs) are frequently dysregulated in various cancers and have been implicated in the etiology and progression of cancer. Ovarian cancer, the most fatal gynecological cancer, has a poor prognosis and a high patient fatality rate due to metastases. In this study, we classified patients with ovarian cancer into three groups based on their ncRNA expression levels. Notably, an ncRNA transcribed by RNA polymerase III, RNA component of mitochondrial RNA processing endoribonuclease (RMRP), is highly expressed in a group with a poor prognosis. Functional assays using SKOV3 and HeyA8 human ovarian cancer cell lines revealed that while RMRP modulation had no significant effect on cell viability, it markedly enhanced cell invasion. Knockdown and ectopic expression experiments demonstrated that RMRP promotes the secretion of matrix metalloproteinase (MMP)-2 and -9, thereby facilitating ovarian cancer cell invasiveness. Transcriptomic analysis further revealed a positive correlation between RMRP expression and genes involved in cellular localization, including RAB31, a member of the Ras-related protein family. Notably, RAB31 knockdown abrogated the pro-invasive effects of RMRP, identifying it as a key downstream effector in SKOV3 and HeyA8 cells. In addition, MechRNA analysis identified RAB31 as a putative RMRP-interacting transcript. These findings establish RMRP as a critical regulator of RAB31-dependent MMP secretion and ovarian cancer cell invasion. Moreover, our results suggest that RMRP could serve as a promising prognostic biomarker for ovarian cancer.

Hypoxia-induced PRPF19 modulates TPT1 alternative splicing to facilitate cisplatin resistance in high-grade serous ovarian cancer

High-grade Serous Ovarian Cancer (HGSOC) is the most common and lethal subtype of ovarian cancer, and chemoresistance is a significant obstacle to its prognosis. The DNA damage response is one of the important mechanisms contributing to chemoresistance. Pre-mRNA processing factor 19 (PRPF19) is essential in DNA damage repair as it can recruit DNA repair proteins. However, the functional role of PRPF19 in HGSOC, especially in chemoresistance, has not been investigated. Herein, we demonstrated that PRPF19 was highly expressed in HGSOC and was associated with poor prognosis. Knockdown of PRPF19 inhibited HGSOC cell proliferation and tumor growth in vivo. In cisplatin-resistant HGSOC cell lines, we observed that knockdown of PRPF19 enhanced cell sensitivity to cisplatin. Mechanistically, PRPF19 silencing induced DNA damage in HGSOC cells, leading to DNA double-strand breaks and ɣH2AX nuclear lesion formation. In addition, mRNA-seq analysis revealed that overexpression of PRPF19 modulates alternative splicing of TPT1, thereby upregulating its expression. Notably, we found that PRPF19 was upregulated under hypoxia. Further examination revealed that hypoxia-inducible factor (HIF)-1α bound to PRPF19 and upregulated PRPF19 expression. In conclusion, these findings suggest that PRPF19 exerts a tumor-promoting effect in HGSOC and may be a novel target for overcoming chemoresistance.

FOXF1 promotes ovarian cancer metastasis by facilitating HMGA2-mediated USP30-dependent S100A6 deubiquitination

Ovarian cancer is the most common type of gynecological malignant tumor, with the highest mortality rate among female genital malignant tumors. In this study, we initially identified forkhead box F1 (FOXF1) as a potential prognostic biomarker of ovarian cancer through bioinformatics analysis. FOXF1 expression was higher in ovarian cancer tissue samples and served as an unfavorable prognostic factor. In vitro and in vivo experiments demonstrated that FOXF1 enhanced ovarian cancer cell migration and tumor dissemination. Chromatin immunoprecipitation-polymerase chain reaction and luciferase assays revealed that FOXF1 bound directly to the high-mobility group AT-hook 2 (HMGA2) promoter and significantly induced its transcriptional activity. Subsequent co-immunoprecipitation and mass spectrometry analyses demonstrated that HMGA2 stabilized S100 calcium-binding protein A6 (S100A6) protein through recruitment of the deubiquitinase, ubiquitin-specific peptidase 30 (USP30), thereby inhibiting S100A6 degradation. Rescue experiments further illustrated that FOXF1 induced ovarian cancer cell mobility in an HMGA2/S100A6-dependent manner. Additionally, FOXF1, HMGA2, USP30, and S100A6 were clinically relevant in patients with ovarian cancer. This is the first study to reveal the molecular mechanisms underlying FOXF1-mediated ovarian cancer metastasis and demonstrate that FOXF1 represents a potential therapeutic target in patients with metastatic ovarian cancer.

LARP1, an RNA-binding protein, participates in ovarian cancer cell survival by regulating mitochondrial oxidative phosphorylation in response to the influence of the PI3K/mTOR pathway

Targeting the PI3K/mTOR pathway and modulating mitochondrial adaptation is expected to be a critical approach for cancer therapy. Although the regulation of mitochondria by the PI3K/mTOR pathway has been investigated, it is not well understood due to the complexity of its regulatory mechanisms. RNA-binding proteins (RBPs) selectively regulate gene expression through post-transcriptional modulation, playing a key role in cancer progression. LARP1, a downstream RBP of the mTOR pathway, is involved in mitochondria-mediated BCL-2 cell survival. Therefore, exploring the involvement of LARP1 in PI3K/mTOR-mediated translational regulation of mitochondria-associated proteins in ovarian cancer cells could help elucidate the role of mitochondria in the PI3K/mTOR pathway. We found that, unlike SKOV3 cells, the mitochondrial function of A2780 cells was not affected, which were insensitive to the dual PI3K/mTOR inhibitor PKI-402, suggesting that cell survival may be related to mitochondrial function. Knockdown of the LARP1 gene after PKI-402 treatment resulted in impaired mitochondrial function in A2780 cells, possibly due to decreased mRNA stability and reduced protein translation of the mitochondrial transcription initiation factor, TFB2M, and the respiratory chain complex II subunit, SDHB. LARP1 affects protein translation by binding to TFB2M mRNA, regulating mitochondrial DNA-encoded genes, or indirectly regulating the nuclear DNA-encoded SDHB gene, ultimately interfering with mitochondrial oxidative phosphorylation and leading to apoptosis. Therefore, LARP1 may be an important mediator in the PI3K/mTOR pathway for regulating mRNA translation and mitochondrial function. Targeting RBPs such as LARP1 downstream of the mTOR pathway may provide new insights and potential therapeutic approaches for ovarian cancer treatment.

Integrative analysis of single-cell and bulk transcriptomes reveals metabolic heterogeneity and identifies PFKP as a therapeutic target in cervical cancer

Cervical cancer (CC) is still a major gynecological tumor among women globally. The heterogeneity landscape and prognostic value of metabolic reprogramming in CC remain unclear. Our research first uncovered metabolic heterogeneity and identified three distinct metabolic subtypes in CC. Based on transcriptomic differences between metabolic subtypes, we developed a robust prognostic signature (TPM3, MAP7, PFKP, IL3RA, ISCU) using machine learning, which robustly stratified patient risk. CC patients with higher risk scores presented unfavorable outcomes and showed an immunosuppressive status. Functional experiments confirmed that phosphofructokinase, platelet (PFKP) promotes CC proliferation and glycolysis. Moreover, we demonstrated that Suramin effectively suppressed CC tumor growth by inhibiting PFKP-mediated glycolysis. Our findings provide a robust prognostic model and disclose PFKP as a potential therapeutic target in CC, offering insightful guidance on cancer management of CC patients.

Astragalus polysaccharide hinders cervical cancer immune escape by targeting NR3C2 and activating SLC40A1

Astragalus polysaccharides (APS) show promising effects in preventing tumor progression and immune escape. This study investigated the mechanism of APS in immune escape in cervical cancer (CC). The effects of different APS concentrations on the viability of CC cell lines (HeLa and SiHa) were determined. Immune evasion by CC cells was examined after APS treatment. An in vivo model was constructed by subcutaneous injection of U14 cells, and the effect of APS on immune evasion was investigated. APS downstream targets were screened using multiple databases, and the regulatory relationship between APS and NR3C2 was verified. Bioinformatics analysis was conducted to identify the downstream molecules of NR3C2, and the regulatory mechanism was validated. The effects of NR3C2 and SLC40A1 on immune escape were tested in vivo and in vitro. APS inhibited immune escape in CC and activated NR3C2 expression and CD8

Expression of CREB3L1 blocks key cancer pathways and suppresses metastasis of lung squamous cell carcinoma cells

Metabolic adaptation in epithelial ovarian cancer metastasis

Epithelial ovarian cancer (EOC) is highly lethal due to its unique metastatic characteristics. EOC spheroids enter a non-proliferative state, with hypoxic cores and reduced oncogenic signaling, all of which contribute to tumour dormancy during metastasis. We investigated the metabolomic states of EOC cells progressing through the three steps to metastasis. Metabolomes of adherent, spheroid, and re-adherent cells were validated by isotopic metabolic flux analysis and mitochondrial functional assays to identify metabolic pathways that were previously unknown to promote EOC metastasis. Although spheroids were thought to exist in a dormant state, metabolomic analysis revealed an unexpected upregulation of energy production pathways in spheroids, accompanied by increased abundance of tricarboxylic acid (TCA) cycle and electron transport chain proteins. Tracing of

PUMA overexpression dissociates thioredoxin from ASK1 to activate the JNK/BCL-2/BCL-XL pathway augmenting apoptosis in ovarian cancer

ASK1-JNK signaling promotes mitochondrial dysfunction-mediated apoptosis, but the bridge between JNK and apoptosis is not fully understood. PUMA induces apoptosis through BAX/BAK. Our previous study suggests a therapeutic potential of PUMA for ovarian cancer. However, whether and how PUMA activates ASK1 remains unclear. Here, we found for the first time that PUMA activated ASK1 by dissociating thioredoxin (TRX) from ASK1, however, it neither interacted with ASK1 nor TRX. Furthermore, PUMA overexpression caused ROS release from mitochondrial. H

Comprehensive analysis of ceRNA networks in HPV16- and HPV18-mediated cervical cancers reveals XIST as a pivotal competing endogenous RNA

Cervical cancer (CC) is one of the most common cancers in women worldwide, being closely related to high-risk human papillomavirus (HR-HPVs). After a particular HR-HPV infects a cervical cell, transcriptional changes in the host cell are expected, including the regulation of lncRNAs, miRNAs, and mRNAs. Such transcripts may work independently or integrated in complex molecular networks - as in competing endogenous RNA (ceRNA) networks. In our research, we gathered transcriptome data from samples of HPV16/HPV18 cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), from The Cancer Genome Atlas (TCGA) project. Using GDCRNATools, we identified ceRNA networks that differentiate HPV16- from HPV18-mediated CESC. For HPV16-CESC, three lncRNA-mRNA co-expressed pairs were reported, all led by the X-inactive specific transcript (XIST): XIST | DLG5, XIST | LGR4, and XIST | ZNF81. The XIST | LGR4 and XIST | ZNF81 pairs shared 11 miRNAs, suggesting an increased impact on their final biological effect. XIST also stood out as an important lncRNA in HPV18-CESC, leading 35 of the 42 co-expressed pairs. Some mRNAs, such as ADAM9 and SLC38A2, emerged as important players in the ceRNA regulatory networks due to sharing a considerable amount of miRNAs with XIST. Furthermore, some XIST-associated axes, namely XIST | miR-23a-3p | LGR4 and XIST | miR-30b-5p or miR-30c-5p or miR-30e-5p I ADAM9, had a significant impact on the overall survival of HPV16- and HPV18-CESC patients, respectively. Together, these data suggest that XIST has an important role in HPV-mediated tumorigenesis, which may implicate different molecular signatures between HPV16 and HPV18-associated tumors.

Retinoic acid receptor-beta prevents cisplatin-induced proximal tubular cell death

Cisplatin's toxicity in renal tubular epithelial cells limits the therapeutic efficacy of this antineoplastic drug. In cultured human proximal tubular HK-2 cells (PTC) a prostaglandin uptake transporter (PGT)-dependent increase in intracellular prostaglandin E