Bcl2l10 induces metabolic alterations in ovarian cancer cells by regulating the TCA cycle enzymes SDHD and IDH1

Abstract

Bcl2-like-10 (Bcl2l10) has both oncogenic and tumor suppressor functions depending on the type of cancer. It has been previously demonstrated that the suppression of Bcl2l10 in ovarian cancer SKOV3 and A2780 cells causes cell cycle arrest and enhances cell proliferation, indicating that Bcl2l10 is a tumor suppressor gene in ovarian cancer cells. The aim of the present study was to identify possible downstream target genes and investigate the underlying mechanisms of action of Bcl2l10 in ovarian cancer cells. RNA sequencing (RNA-Seq) was performed to obtain a list of differentially expressed genes (DEGs) in Bcl2l10-suppressed SKOV3 and A2780 cells. The RNA-Seq data were validated by reverse transcription-quantitative PCR (RT-qPCR) and western blot analysis, and the levels of metabolites after Bcl2l10-knockdown were measured using colorimetric assay kits. Pathway enrichment analysis revealed that the commonly downregulated genes in SKOV3 and A2780 cells after Bcl2l10-knockdown were significantly enriched in metabolic pathways. The analysis of the DEGs identified from RNA-Seq and validated by RT-qPCR revealed that succinate dehydrogenase complex subunit D (SDHD) and isocitrate dehydrogenase 1 (IDH1), which are key enzymes of the TCA cycle that regulate oncometabolite production, may be potential downstream targets of Bcl2l10. Furthermore, Bcl2l10-knockdown induced the accumulation of succinate and isocitrate through the downregulation of SDHD and IDH1. The present study was the first to elucidate the metabolic regulatory functions of Bcl2l10 in ovarian cancer cells, and the results indicated that Bcl2l10 may serve as a potential therapeutic target in ovarian cancer.

Deregulated Metabolic Pathways in Ovarian Cancer: Cause and Consequence

“…Succinate dehydrogenase complex subunit D (SDHD) and IDH1 were regulated by Bcl2l10. Knocking down Bcl2l10 downregulated IDH1 and SDHD and led to the accumulation of oncometabolites such as succinate and isocitrate, and therefore lead to the promotion and progression of ovarian cancer [121]. Succinate dehydrogenase is another enzyme that is a part of the TCA cycle and is primarily involved in the catalytic conversion of succinate to fumarate by oxidation [122].…”

Unraveling Autocrine Signaling Pathways through Metabolic Fingerprinting in Serous Ovarian Cancer Cells

“…A recent study has shown the differential sensitivity of low-grade serous ovarian carcinoma cells and HGSOC cells to mTOR inhibitors [ 54 ]. Previous studies from several laboratories including ours have demonstrated the role of atypical signaling pathways such as those regulated by LPA and BCL20 in modulating the glucose metabolism in cancer cells [ 16 , 55 , 56 ]. Further interrogation of these signaling pathways in relation to specific metabolites should identify the mechanism(s) involved in the differential modulation of TCA cycle and aerobic glycolysis in these cell lines.…”