FABP5 coordinates lipid signaling that promotes prostate cancer metastasis

Abstract

Prostate cancer (PCa) is defined by dysregulated lipid signaling and is characterized by upregulation of lipid metabolism-related genes including fatty acid binding protein 5 (FABP5), fatty acid synthase (FASN), and monoacylglycerol lipase (MAGL). FASN and MAGL are enzymes that generate cellular fatty acid pools while FABP5 is an intracellular chaperone that delivers fatty acids to nuclear receptors to enhance PCa metastasis. Since FABP5, FASN, and MAGL have been independently implicated in PCa progression, we hypothesized that FABP5 represents a central mechanism linking cytosolic lipid metabolism to pro-metastatic nuclear receptor signaling. Here, we show that the abilities of FASN and MAGL to promote nuclear receptor activation and PCa metastasis are critically dependent upon co-expression of FABP5 in vitro and in vivo. Our findings position FABP5 as a key driver of lipid-mediated metastasis and suggest that disruption of lipid signaling via FABP5 inhibition may constitute a new avenue to treat metastatic PCa.

The FABP12/PPARγ pathway promotes metastatic transformation by inducing epithelial‐to‐mesenchymal transition and lipid‐derived energy production in prostate cancer cells

“…The biological actions of these FABPs in promoting PCa progression appear to be synergic rather than redundant and mediated through distinct pathways. The most extensively studied FABP in PCa, FABP5, promotes PCa cell and/or xenograft tumor growth, with inhibition of both PPARb/d and PPARc suppressing these effects [30,33,[69][70][71][72][73]. FABP5 has been proposed to promote PCa metastasis by triggering angiogenesis (VEGF induction) [71,74] and fatty acid synthesis [33].…”

“…FABPs are receiving increasing attention in the field of oncology because of their demonstrated roles in cancer progression, and proposed roles in the prevention and treatment of cancer [26][27][28][29], particularly as related to PPAR function [30,31]. While a number of studies point to FABP involvement in PCa metastasis [32][33][34], the precise mechanism underlying FABP action remains elusive. Particularly, the roles of FABPs in epithelial-to-mesenchymal transition (EMT), a priming process leading to metastasis of epithelium-derived carcinomas [35], and dysregulation of energy production, a critical event promoting metastasis in various cancer types [13,14], have yet to be determined in PCa.…”

Fatty acid binding protein 5 forms higher order assemblies with FLAP or COX-2 in LPS-stimulated macrophages

“…It is increasingly recognized that FABPs, and in particular FABP5, play roles in both assembling signaling complexes and simultaneously transferring substrates that play an important role in signaling. FABP5 links the function of fatty acid synthase (FASN) and monoacylglycerolipase (MAGL) to signaling by delivering lipid activators to nuclear hormone receptors including PPARδ and estrogen-related receptor α (ERRα) (25, 26). FABP5 is also responsible for the integrity of the mitochondria in lipid metabolism in regulatory T cells (27).…”

The Lipolysome—A Highly Complex and Dynamic Protein Network Orchestrating Cytoplasmic Triacylglycerol Degradation

“…Overexpression of MGL significantly increased PPAR gamma activity to promote a metastatic phenotype, while epidermal FABP knockdown attenuated PPAR gamma even in cells overexpressing MGL. However, functional studies to investigate whether direct protein-protein interaction is needed for this process have not been carried out [192]. Interestingly, other studies demonstrated that HSL and ABHD5 interact only with distinct FABPs.…”