eIF3a Regulates De Novo Fatty Acid Synthesis as an Alternative Mechanism in Cisplatin Response in Non-Small Cell Lung Cancer Cells

Abstract

eIF3a is known to modulate DNA damage repair and cancer chemotherapy resistance partially via translational regulation of Raptor and its downstream mTOR pathway activity. Fatty acid synthase (FASN) has recently been reported to exert negative feedback on the mTOR signaling pathway, and FASN overexpression is associated with reduced chemotherapy efficiency in multiple cancer types. Here, we show that eIF3a exerts additional regulation on mTOR signaling pathway and chemotherapy resistance in non-small cell lung cancer by inhibiting FASN-mediated de novo lipid synthesis. Through genetic and chemical manipulations, we demonstrate that eIF3a physically interacts with the 5’-UTR of FASN mRNA to prevent FASN protein synthesis. Furthermore, FASN downregulation by eIF3a results in accumulation of malonyl-CoA, a substrate for fatty acid synthesis, which in turn directly inhibits mTOR activity of mTORC1 complex, decreasing NER protein level and cellular sensitivity to cisplatin in an eIF3a-dependent manner in addition to eIF3a-regulated expression of Raptor subunit in mTORC1. Taken together, our findings reveal a direct translational control of FASN-mediated fatty acid metabolism, suggesting a multi-level eIF3a regulatory paradigm on NER protein synthesis and activity during cancer cell response to cisplatin treatment.