PGC‐1α inhibits polyamine metabolism in Cyclin E1‐driven ovarian cancer

Abstract

Abstract Aim Cyclin E1‐driven ovarian cancer (OvCa) is characterized with metabolic shift. In this study, we aim to pinpoint the metabolic pathway altered and assess its therapeutic potential. Methods In silico reproduction of TCGA ovarian cancer dataset and functional annotation using GSEA was performed. Candidate metabolic pathway was validated using in vitro and in vivo assays. Results From TCGA database, we found that polyamine metabolism was significantly enriched in Cyclin E1‐driven OvCa. Expressions of SMS, SRM, and ODC1 were positively correlated with that of CCNE1, respectively. ODC1 and SMS expressions were significantly correlated with decreased immune infiltrates. PGC‐1α silencing significantly decreased invasion and migration in both OvCa cell lines. Both spermidine and spermine levels were significantly increased when PGC‐1α was silenced. Targeting SRM significantly decreased spermine level in OVCAR3 cells, which was rescued when PGC‐1α was silenced. Silencing of PGC‐1α resulted in increased SRM in both OvCa cells. Dinaciclib significantly decreased invasion and migration of OVCAR3 cells. Expressions of PD‐L1 and PD‐L2 were predominantly in tumor‐infiltrating lymphocytes. Dinaciclib showed no notable effect of PD‐1 yet substantially induced the increased levels of PD‐L1 and PD‐L2. Conclusion Cyclin E1‐driven OvCa is characterized with activated polyamine synthesis, which is associated with decreased cancer immunity. Targeting polyamine and CDK2 may therefore sensitize this genotype to immune checkpoint blockade.

Keywords

• CCNE1
• High‐grade serous ovarian cancer
• polyamine metabolism