Inhibition of collagen XI alpha 1-induced fatty acid oxidation triggers apoptotic cell death in cisplatin-resistant ovarian cancer

Sameera Nallanthighal,Jessica Sage,Sandra Orsulic,Jennifer Cha,James Patrick Heiserman,Chaitali Korgaonkar,Bo Zhou,Christina Terpsithea Hanos,Ye Hu,Miran Rada,Kenneth Norman,Wei Yang,Dong-Joo Cheon,Zahra Ashkavand

doi:10.1038/s41419-020-2442-z

Abstract

Collagen type XI alpha 1 (COL11A1) is a novel biomarker associated with cisplatin resistance in ovarian cancer. However, the mechanisms underlying how COL11A1 confers cisplatin resistance in ovarian cancer are poorly understood. We identified that fatty acid β-oxidation (FAO) is upregulated by COL11A1 in ovarian cancer cells and that COL11A1-driven cisplatin resistance can be abrogated by inhibition of FAO. Furthermore, our results demonstrate that COL11A1 also enhances the expression of proteins involved in fatty acid synthesis. Interestingly, COL11A1-induced upregulation of fatty acid synthesis and FAO is modulated by the same signaling molecules. We identified that binding of COL11A1 to its receptors, α1β1 integrin and discoidin domain receptor 2 (DDR2), activates Src-Akt-AMPK signaling to increase the expression of both fatty acid synthesis and oxidation enzymes, although DDR2 seems to be the predominant receptor. Inhibition of fatty acid synthesis downregulates FAO despite the presence of COL11A1, suggesting that fatty acid synthesis might be a driver of FAO in ovarian cancer cells. Taken together, our results suggest that COL11A1 upregulates fatty acid metabolism in ovarian cancer cells in a DDR2-Src-Akt-AMPK dependent manner. Therefore, we propose that blocking FAO might serve as a promising therapeutic target to treat ovarian cancer, particularly cisplatin-resistant recurrent ovarian cancers which typically express high levels of COL11A1.

Highlights

Introduction TheWarburg effect describes a phenomenon where cancer cells rely on glycolysis for their energy needs even in the presence of oxygen[1]
To investigate whether COL11A1 directly upregulates the expression of fatty acid β-oxidation (FAO) enzymes in ES2, OVCAR3, and A2780 ovarian cancer cells that do not express COL11A1 or express very low endogenous levels of COL11A131, we (i) co-cultured ES2 ovarian cancer cell line with scrambled control cancer-associated fibroblasts (CAFs) or COL11A1-knockdown CAFs; (ii) cultured ES2, OVCAR3 and A2780 ovarian cancer cell lines in plates coated with COL11A1 extracted from A204 cell line (COL11A1 extract); or (iii) supplemented ES2 cells with recombinant COL11A1 protein
COL11A1 increased the levels of ATP and NADH, byproducts of FAO, in ES2 cells cultured on COL11A1 extract (Fig. 1E), which was attenuated by CPT1A knockdown using short hairpin RNAs (shRNAs) (Fig. 1E, S1F-G) or treatment with a pharmacological inhibitor of CPT1A, etomoxir (Fig. S2A, B)

Summary

Introduction

Warburg effect describes a phenomenon where cancer cells rely on glycolysis for their energy needs even in the presence of oxygen[1]. Increasing evidence suggests that other metabolic pathways play important roles in supplying energy and biomass to cancer cells[2,3,4]. Rapidly proliferating cancer cells rely on large amounts of fatty acids to support various biological processes including membrane formation and signaling. Fatty acid metabolism is important for ovarian cancer cells as they frequently disseminate to fat-rich omentum and uptake fatty acids for their growth and survival[23,24]. The molecular mechanisms by which ovarian cancer cells switch their metabolic phenotype to promote fatty acid metabolism and chemotherapy resistance are largely unknown

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Results

Conclusion