Abstract
Epidermal or cutaneous fatty acid-binding protein is an intracellular lipid-binding protein, also known as FABP5, and its expression level is closely related to cancer cell proliferation and metastatic activities in various types of carcinoma. However, the molecular mechanisms of FABP5 in cancer cell proliferation and its other functions have remained unclear. In the present study, we have clearly revealed that FABP5 activated expression of metabolic genes (ATP5B, LCHAD, ACO2, FH and MFN2) via a novel signaling pathway in an ERRα (estrogen-related receptor α)-dependent manner in prostate cancer cell lines. To clarify the novel function of FABP5, we examined the activation mechanisms of the ERRα target genes via FABP5. A direct protein-protein interaction between FABP5 and ERRα was demonstrated by immunoprecipitation and GST pull-down assays. We have clearly revealed that FABP5 interacted directly with transcriptional complex containing ERRα and its co-activator PGC-1β to increase expression of the ERRα target genes. In addition, we have shown that FABP5 knockdown induced high energy stress leading to induction of apoptosis and cell cycle arrest via AMPK-FOXO3A signaling pathway in prostate cancer cells, suggesting that FABP5 plays an important role in cellular energy status directing metabolic adaptation to support cellular proliferation and survival.
Highlights
Prostate cancer (PCa) is the most common cancer in men worldwide and the second leading cause of male cancer-related deaths in the United States [1, 2]
We have clearly revealed that fatty acid-binding protein 5 (FABP5) activated expression of metabolic genes (ATP5B, long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), aconitase 2 (ACO2), fumarate hydratase (FH) and mitofusin 2 (MFN2)) via a novel signaling pathway in an estrogenrelated receptor α (ERRα)-dependent manner in prostate cancer cell lines
Compensatory effects by other fatty acid-binding proteins (FABPs) might not occur in this experimental condition, because the expression levels of other FABPs were not affected by FABP5 knockdown (Supplementary Figure 1F)
Summary
Prostate cancer (PCa) is the most common cancer in men worldwide and the second leading cause of male cancer-related deaths in the United States [1, 2]. Lower rates of glycolysis and higher rates of fatty acid oxidation have been characterized in PCa cells. Understanding the regulation of fatty acid metabolism in PCa is important for developing novel therapeutic strategies and diagnostic tools. Recent studies have reported that FABPs play important roles in the regulation of gene expression, cell growth www.oncotarget.com and differentiation [10, 11]. Multiple reports have demonstrated that metabolic reprogramming is necessary to sustain cancer cell growth and survival [12,13,14]. Since fatty acids are required as an energy source, the formation of membrane components, and the production of cellular signaling molecules during cancer cell proliferation, FABPs might play an important role in cell proliferation in cancer cells [15]
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