Ether-linked phosphatidylethanolamine is a chemo-desensitizer of human carcinomas and epithelial ovarian cancer cells

Abstract

Abstract Background Lipid reprogramming in carcinoma is reported to have a role in carcinogenesis, prognosis, and therapy response. Autonomous or nonautonomous resources may contribute to lipid reprogramming. Nonautonomous lipid resources contributed by lipoproteins and their receptors have been reported in epithelial ovarian cancer (EOC), but the impact of autonomous lipid metabolites is unknown. This report reveals that a unique lipid class, ether-linked phosphatidylethanolamine (PE O–), enhanced chemoinsensitivity and progression in EOC, and potentially in other carcinomas. Method Unbiased bioinformatics analyses of data from the carcinoma databases CCLEC (Cancer Cell Line Encyclopedia Consortium) and GDSCC (Genomics of Drug Sensitivity in Cancer Consortium) and an in-house lipidomic database of human carcinoma lines were performed to identify relationships with chemoagent cytotoxicity. EOC cells (SKOV3 and OVCAR3) were treated with PE O– and/or alkylglycerone phosphate synthase (AGPS), an ether lipid-producing enzyme, inhibitor to observe cell growth, mobility, and chemosensitivity. The clinical impact of PE O– metabolic gene expression was determined by analysis of The Cancer Genome Atlas transcriptome to find an association with various clinical features of EOC. Results Glycerophospholipids were the consensus lipid class in lipid metabolism gene and chemosensitivity association analyses of the CCLEC/GDSCC database. In the lipidome database analyses of in-house human carcinoma cell lines, the glycerophospholipid, PE O–, was identified as the dominant lipid associated with cisplatin/paclitaxel sensitivity. In various hypothesis-driven cisplatin/paclitaxel sensitivity analyses of cell line lipidomes, PE O– remained the dominant lipid class. Tests of the effects of PE O– on cancer phenotypes showed that it enhanced cell growth and migratory activities and promoted insensitivity to cisplatin/paclitaxel. However, the AGPS inhibitor sensitized EOC cells to the chemocytotoxic effects of cisplatin/paclitaxel, whereas treatment with PE O– reversed this effect. Analysis of a TCGA-EOC transcriptome database showed that PE O– gene expression was positively correlated with progression in general or in those treated with platin- or taxel-based chemotherapies. Conclusion The expression of PE O– synthesis genes aggravated negative responses of EOC patients to therapy. PE O– facilitated human carcinoma cell line growth, mobility, and chemoinsensitivity.