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

Abstract

Early stage localized prostate cancer (PCa) has an excellent prognosis; however, patient survival drops dramatically when PCa metastasizes. The molecular mechanisms underlying PCa metastasis are complex and remain unclear. Here, we examine the role of a new member of the fatty acid-binding protein (FABP) family, FABP12, in PCa progression. FABP12 is preferentially amplified and/or overexpressed in metastatic compared to primary tumors from both PCa patients and xenograft animal models. We show that FABP12 concurrently triggers metastatic phenotypes (induced epithelial-to-mesenchymal transition (EMT) leading to increased cell motility and invasion) and lipid bioenergetics (increased fatty acid uptake and accumulation, increased ATP production from fatty acid b-oxidation) in PCa cells, supporting increased reliance on fatty acids for energy production. Mechanistically, we show that FABP12 is a driver of PPARc activation which, in turn, regulates FABP12's role in lipid metabolism and PCa progression. Our results point to a novel role for a FABP-PPAR pathway in promoting PCa metastasis through induction of EMT and lipid bioenergetics.

An Amplified Fatty Acid-Binding Protein Gene Cluster in Prostate Cancer: Emerging Roles in Lipid Metabolism and Metastasis

“…A separate study from this one has also shown independence of FABP5 expression from PCa clinical outcomes [49]. reported to be highly expressed in PCa [51], and we have studied and proposed a role for FABP12 in promoting PCa metastasis and progression (discussed below) [29]. Human PCa disease-free (DF) patient survival analysis based on mRNA levels of each FABP located at 8q21.13.…”

“…These promising results, combined with the documented roles of FABPs in cancer progression, support further development of FABP-targeted inhibitors and therapies for the treatment of PCa. acid synthesis, lipolysis and angiogenesis pathways [48,76,93,139], whereas FABP12 induces EMT and oxidative phosphorylation [29]. PPARs are important mediators of FABP functions presumably through fatty acid transfer from FABPs to PPARs, although the details remain elusive.…”

“…FABP8 (PMP2) has been shown to be associated with melanoma invasion [ 50 ]. FABP9 has been reported to be highly expressed in PCa [ 51 ], and we have studied and proposed a role for FABP12 in promoting PCa metastasis and progression (discussed below) [ 29 ].…”

“…We have recently found that FABP12, enriched in metastatic PCa tumors from patients as well as a xenograft mouse model, induces lipid droplet formation in PCa cells cultured in both normal media and medium supplemented with oleic acid [ 29 ]. FABP12 also enhances FASN expression (our unpublished data), pointing to a role for FABP12 in promoting intracellular lipid accumulation through both elevated fatty acid uptake from the microenvironment and de novo synthesis, both of which may be essential to potentiate PCa metastasis.…”

“…FABPs are receiving increasing attention in oncology because of their emerging roles in the prevention and treatment of cancer [ 21 , 22 ]. In particular, FABPs are implicated in metastatic progression in various cancers [ 23 , 24 , 25 , 26 ], including prostate cancer [ 27 , 28 , 29 ]. They are also recognized as important factors in metabolic diseases [ 30 , 31 , 32 ], particularly as related to PPAR (peroxisome proliferator-activated receptor) function [ 33 , 34 , 35 , 36 , 37 , 38 ].…”