De Novo Palmitate Synthesis Supports Oncogenic Signalling and Tumor Growth Through Diverse Mechanisms: Implications for FASN-Targeted Therapeutics

Abstract

Palmitate, the enzymatic product of fatty acid synthase (FASN), provides a substrate for the synthesis of longand short-chain fatty acids. Many recent studies have expanded our knowledge about the roles palmitate and lipid synthesis play in tumor cell biology beyond supporting energy metabolism and membrane building [1,2]. The recent article by Ventura and colleagues [3] described cell biology and pharmacology studies using a novel, selective small molecule FASN inhibitor, TVB-3166. They demonstrated that FASN inhibition disrupts oncogenic signalling and tumor growth in xenograft models through inhibition of pathways that include Wnt/beta-catenin and expression of cMyc: potent oncogenes historically recalcitrant to direct pharmacological inhibition. Discussed here is how these findings advance our mechanistic understanding of the diverse biological roles of palmitate and its integration into various signalling pathways driving tumor cell proliferation and survival. These insights highlight the promising potential of selective, potent FASN inhibitors as a novel therapeutic strategy for cancer and other illnesses.

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“…Fatty acid synthase plays an important role in tumor cell development and survival because it provides palmitic acids needed for the synthesis of membrane phospholipids during rapid cell growth and proliferation. Moreover, endogenously synthesized fatty acids act as posttranslational protein modifiers and modulate gene expression (24). Palmitate and palmitate-derived lipids are known to play essential roles in modulating signal transduction and function of proteins associated with signaling pathways that regulate cell growth and survival (24).…”

“…Moreover, endogenously synthesized fatty acids act as posttranslational protein modifiers and modulate gene expression (24). Palmitate and palmitate-derived lipids are known to play essential roles in modulating signal transduction and function of proteins associated with signaling pathways that regulate cell growth and survival (24). Furthermore, recent studies have suggested that endogenously synthesized fatty acids are utilized by β-oxidation in CRC cells, which supports cancer cell survival, particularly under conditions of energy stress (8).…”

“…Of course, these processes are essentially related to FASN activity. Several studies have revealed important connections between lipid synthesis pathways and ER stress response (18,37) , lipid metabolism, microtubule function (38) , and various signaling pathways driving tumor cell proliferation (24). As described above, palmitate is used not only as a substrate for the synthesis of other lipids but also participates in posttranslational modifications of many proteins, affecting their activity.…”

“…Another example concerns the palmitoylation of Wnt proteins which are secreted, palmitoylated glycoproteins important in embryonic development and human cancers. It has been shown that FASN inhibition disrupts oncogenic signaling and tumor growth in xenograft models through the inhibition of pathways that include Wnt/β-catenin and c-Myc (24) .…”