Cholesterol homeostasis modulates platinum sensitivity in human ovarian cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA603116 | ENA |
REPOSITORIES: ENA
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Project description:Here we show that platinum-resistant ovarian cancer cells also show reduced cholesterol biosynthesis, and mostly rely on uptake of exogenous cholesterol for their needs. Expression of FDPS and OSC, enzymes involved in cholesterol synthesis, are decreased both in drug-resistant cells and upon TRAP1 silencing, whereas the expression of LDL receptor, the main mediator of extracellular cholesterol uptake, is increased. Strikingly, treatment with different statins to inhibit cholesterol synthesis reduces cisplatin-induced apoptosis, whereas silencing of LIPG, an enzyme involved in lipid metabolism, increases sensitivity to the drug.
2020-05-21 | GSE144248 | GEO
Project description: Not available
| S-EPMC7226826 | biostudies-literature
Project description:Platinum-based therapy is the standard first-line treatment for high-grade serous ovarian cancer (HGSC). However, most patients develop resistance and recurrence despite an initial response to therapy. Ovarian cancer stem cells (OCSCs) are enriched in recurrent tumors and contribute to platinum resistance. These tumors also show promoter DNA hypermethylation, and DNA methyltransferase inhibitors (DNMTis) have been shown to restore sensitivity in platinum-resistant ovarian cancer cells. Here, we demonstrated that combining DNMTi with platinum prevented the platinum-induced enrichment of OCSCs and identified NF-κB and STAT3 signaling pathways as potential regulators of platinum-induced OCSC enrichment. STAT3 was active at baseline in OC cells and platinum treatment alone activated NF-κB while maintaining STAT3 activity. Platinum combined with DNMTi decreased STAT3 activation, while still inducing NF-κB activation. Knockdown experiments demonstrated that the presence of both NF-κB and STAT3 was necessary for platinum-induced OCSC enrichment. Analysis of STAT3 and NF-κB subunit p65 CUT&RUN data showed increased binding in introns and intergenic regions in response to platinum. Additionally, DNMTi enriched NF-κB binding at endogenous retroviruses (ERVs), which correlated with changes in expression of nearby genes when DNMTi was combined with platinum. We conclude that combining DNMTi with platinum modulates STAT3 and NF-κB activation and genomic binding, potentially influencing target gene expression and preventing platinum-induced enrichment of OCSCs.
2026-06-22 | GSE332978 | GEO
Project description:Platinum-based therapy is the standard first-line treatment for high-grade serous ovarian cancer (HGSC). However, most patients develop resistance and recurrence despite an initial response to therapy. Ovarian cancer stem cells (OCSCs) are enriched in recurrent tumors and contribute to platinum resistance. These tumors also show promoter DNA hypermethylation, and DNA methyltransferase inhibitors (DNMTis) have been shown to restore sensitivity in platinum-resistant ovarian cancer cells. Here, we demonstrated that combining DNMTi with platinum prevented the platinum-induced enrichment of OCSCs and identified NF-κB and STAT3 signaling pathways as potential regulators of platinum-induced OCSC enrichment. STAT3 was active at baseline in OC cells and platinum treatment alone activated NF-κB while maintaining STAT3 activity. Platinum combined with DNMTi decreased STAT3 activation, while still inducing NF-κB activation. Knockdown experiments demonstrated that the presence of both NF-κB and STAT3 was necessary for platinum-induced OCSC enrichment. Analysis of STAT3 and NF-κB subunit p65 CUT&RUN data showed increased binding in introns and intergenic regions in response to platinum. Additionally, DNMTi enriched NF-κB binding at endogenous retroviruses (ERVs), which correlated with changes in expression of nearby genes when DNMTi was combined with platinum. We conclude that combining DNMTi with platinum modulates STAT3 and NF-κB activation and genomic binding, potentially influencing target gene expression and preventing platinum-induced enrichment of OCSCs.
2026-06-22 | GSE319610 | GEO
Project description:Platinum-based therapy is the standard first-line treatment for high-grade serous ovarian cancer (HGSC). However, most patients develop resistance and recurrence despite an initial response to therapy. Ovarian cancer stem cells (OCSCs) are enriched in recurrent tumors and contribute to platinum resistance. These tumors also show promoter DNA hypermethylation, and DNA methyltransferase inhibitors (DNMTis) have been shown to restore sensitivity in platinum-resistant ovarian cancer cells. Here, we demonstrated that combining DNMTi with platinum prevented the platinum-induced enrichment of OCSCs and identified NF-κB and STAT3 signaling pathways as potential regulators of platinum-induced OCSC enrichment. STAT3 was active at baseline in OC cells and platinum treatment alone activated NF-κB while maintaining STAT3 activity. Platinum combined with DNMTi decreased STAT3 activation, while still inducing NF-κB activation. Knockdown experiments demonstrated that the presence of both NF-κB and STAT3 was necessary for platinum-induced OCSC enrichment. Analysis of STAT3 and NF-κB subunit p65 CUT&RUN data showed increased binding in introns and intergenic regions in response to platinum. Additionally, DNMTi enriched NF-κB binding at endogenous retroviruses (ERVs), which correlated with changes in expression of nearby genes when DNMTi was combined with platinum. We conclude that combining DNMTi with platinum modulates STAT3 and NF-κB activation and genomic binding, potentially influencing target gene expression and preventing platinum-induced enrichment of OCSCs.
2026-06-22 | GSE319609 | GEO
Project description:Large independent analyses on cancer cell lines followed by functional studies have identified Schlafen 11 (SLFN11), a putative helicase, as the strongest predictor of sensitivity to DNA-damaging agents (DDA), including platinum. However, its role as a prognostic biomarker is undefined, partially due to the lack of validated methods to score SLFN11 in human tissues. Here, we implemented a pipeline to quantify SLFN11 in human cancer samples. By analyzing a cohort of high-grade serous ovarian carcinoma (HGSOC) specimens prior platinum-based chemotherapy treatment, we show, for the first time, that SLFN11 density in both the neoplastic and microenvironmental components was independently associated with favorable outcome. We observed SLFN11 expression in both infiltrating innate and adaptive immune cells, and analyses in a second, independent, cohort revealed that SLFN11 is associated with immune activation in HGSOC. We found that platinum treatments activated immune-related pathways in ovarian cancer cells in a SLFN11-dependent manner, representative of tumor-immune transactivation. Moreover, SLFN11 expression was induced in activated, isolated, immune cell subpopulations, hinting that SLFN11 in the immune compartment may be an indicator of immune transactivation. In summary, we propose SLFN11 is a dual biomarker capturing simultaneously interconnected immunological and cancer-cell-intrinsic functional dispositions associated with sensitivity to DDA treatment.
2021-07-13 | GSE179896 | GEO
Project description:Mitotic MTH1 Inhibitor Karonudib Kills Epithelial Ovarian Cancer Independent of Platinum Sensitivity
| PRJNA1245156 | ENA
Project description:The objective of this work was to identify potential cancer biomarkers by analyzing microarray and protein expression data from platinum-sensitive and -resistant ovarian cancer patient samples. The gene expression profiles of the samples were ompared based on platinum sensitivity status and PARP levels.
2018-05-09 | GSE114206 | GEO
Project description:The prognosis for women with ovarian cancer (OC) is particularly poor if resistance to platinum compounds, the mainstay of standard-of-care OC therapy, develops. Inhibitors of the Nudix hydrolase MuT homolog 1 (MTH1) have previously been shown to arrest cancer cells in mitosis, increase 8-oxo-2’-deoxyguanosine (8-oxo-dG) incorporation into DNA, and selectively kill neoplastic cells while sparing normal cells. Here we explored the cytotoxic mechanism of these agents as well as their activity against platinum-resistant OC in vitro and in vivo. Two mitotic MTH1 inhibitors (mMTH1is), TH588 and karonudib, decreased colony formation and induced cell death in both platinum-sensitive OC cell lines and their platinum-resistant counterparts in vitro but had limited effects on fallopian tube and immortalized ovarian surface epithelial cells. Treatment with karonudib stalled OC cells in mitosis and caused elevated 8-oxo-dG levels in DNA. Cytotoxicity of this agent was blunted by overexpression of the pre-mitotic checkpoint protein CHFR, which inhibits other anti-mitotics, or treatment with the antioxidant N-acetylcysteine, which diminishes nuclear 8-oxo-dG staining, suggesting a role for both mitotic stalling and increased nuclear incorporation of oxidized nucleotides in karonudib efficacy. In three orthotopic OC patient-derived xenograft models, karonudib induced growth delay in vivo. Moreover, addition of karonudib to carboplatin doubled median overall survival in two models and prolonged survival for the duration of the study (110 days) in the third. These results, which demonstrate activity of mMTH1 as monotherapy and in combination with carboplatin in OC, suggest that karonudib-based combinations warrant further investigation as potential therapies for platinum-resistant OC.
2025-07-02 | GSE293549 | GEO
Project description:Essentially, all patients diagnosed with ovarian cancer (OC) are treated with platinum (Pt); however, Pt resistance (Pt-R) rapidly develops. We show OC cells resistant to Pt increase intracellular cholesterol by increasing expression of the high-density lipoprotein (HDL) receptor, scavenger receptor class B type 1 (SR-B1). Expression of SR-B1 was associated with chemoresistance in OC cells and tumors. SR-B1 blockade using synthetic cholesterol-poor HDL-like nanoparticles (HDL NPs) diminished cholesterol uptake leading to cell death of Pt-R OC cells in vitro and suppressed Pt-R OC tumor growth in vivo. Reduced cholesterol accumulation in Pt-R OC cells induced lipid oxidative stress through reduction of glutathione peroxidase 4 (GPx4) expression leading to ferroptosis. Reduction of GPx4 expression in OC cells re-sensitized Pt-R cells to Pt by reducing cholesterol uptake and enhancing the accumulation of lipid reactive oxygen species (L-ROS). Mechanistically, GPx4 knockdown in OC cells was associated with reduced expression of the histone acetyltransferase EP300, leading to reduced H3K27 acetylation around the SREBP2 promoter suppressing its expression. As SREBP2 regulates SR-B1 transcription, these data demonstrate chemoresistance and cancer cell survival under high ROS burden obligates high GPx4 and SR-B1 expression through SREBP2. Targeting SR-B1 to modulate cholesterol uptake inhibits this axis and causes ferroptosis in vitro and in vivo in Pt-R OC.
2024-06-01 | GSE234404 | GEO