Decreased serine biosynthesis identifies a subgroup of platinum resistant ovarian cancers and novel actionable metabolic vulnerabilities
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA735397 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14740426.fastq.gz | Fastqsanger.gz | |||
| SRR14740427.fastq.gz | Fastqsanger.gz | |||
| SRR14740428.fastq.gz | Fastqsanger.gz | |||
| SRR14740429.fastq.gz | Fastqsanger.gz | |||
| SRR14740430.fastq.gz | Fastqsanger.gz |
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Project description:Platinum compounds display clinical activity against a wide variety of solid tumors. However, resistance to these agents is a major limitation in cancer therapy. Reduced platinum uptake and increased platinum export are examples of resistance mechanisms that limit the extent of DNA damage. Here, we report the discovery and characterization of the role of ATP11B, a P-type ATPase membrane protein, in cisplatin resistance. ATP11B gene silencing restored the sensitivity of ovarian cancer cell lines to cisplatin in vitro. Combined therapy of cisplatin and ATP11B-siRNA significantly decreased cancer growth in mice bearing ovarian tumors derived from cisplatin-sensitive and -resistant cells. In vitro mechanistic studies on cellular platinum content and cisplatin efflux-kinetics indicated that ATP11B enhances the export of cisplatin from cells. The co-localization of ATP11B with fluorescent cisplatin and with vesicular trafficking proteins such as syntaxin-6 (STX6) and vesicular associated membrane protein 4 (VAMP4) strongly suggests that ATP11B contributes to secretory vesicular transport of cisplatin from Golgi to plasma membrane. In conclusion, silencing ATP11B expression might be a therapeutic strategy to overcome cisplatin resistance. We performed the transfection of control-siRNA and ATP11B-siRNA to both cisplatin-sensitive A2780-PAR and cisplatin-resistant A2780-CP20 cells respectively.
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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.
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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.
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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.
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Project description:Platinum compounds display clinical activity against a wide variety of solid tumors. However, resistance to these agents is a major limitation in cancer therapy. Reduced platinum uptake and increased platinum export are examples of resistance mechanisms that limit the extent of DNA damage. Here, we report the discovery and characterization of the role of ATP11B, a P-type ATPase membrane protein, in cisplatin resistance. ATP11B gene silencing restored the sensitivity of ovarian cancer cell lines to cisplatin in vitro. Combined therapy of cisplatin and ATP11B-siRNA significantly decreased cancer growth in mice bearing ovarian tumors derived from cisplatin-sensitive and -resistant cells. In vitro mechanistic studies on cellular platinum content and cisplatin efflux-kinetics indicated that ATP11B enhances the export of cisplatin from cells. The co-localization of ATP11B with fluorescent cisplatin and with vesicular trafficking proteins such as syntaxin-6 (STX6) and vesicular associated membrane protein 4 (VAMP4) strongly suggests that ATP11B contributes to secretory vesicular transport of cisplatin from Golgi to plasma membrane. In conclusion, silencing ATP11B expression might be a therapeutic strategy to overcome cisplatin resistance.
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