Abstract
Fatty acid β-oxidation (FAO) is the main bioenergetic pathway in human prostate cancer (PCa) and a promising novel therapeutic vulnerability. Here we demonstrate therapeutic efficacy of targeting FAO in clinical prostate tumors cultured ex vivo, and identify DECR1, encoding the rate-limiting enzyme for oxidation of polyunsaturated fatty acids (PUFAs), as robustly overexpressed in PCa tissues and associated with shorter relapse-free survival. DECR1 is a negatively-regulated androgen receptor (AR) target gene and, therefore, may promote PCa cell survival and resistance to AR targeting therapeutics. DECR1 knockdown selectively inhibited β-oxidation of PUFAs, inhibited proliferation and migration of PCa cells, including treatment resistant lines, and suppressed tumor cell proliferation and metastasis in mouse xenograft models. Mechanistically, targeting of DECR1 caused cellular accumulation of PUFAs, enhanced mitochondrial oxidative stress and lipid peroxidation, and induced ferroptosis. These findings implicate PUFA oxidation via DECR1 as an unexplored facet of FAO that promotes survival of PCa cells.
Highlights
Prostate cancer (PCa) is the most prevalent male cancer and the second leading cause of cancer deaths in men in Western societies (Bray et al, 2018)
Using our well-defined patient derived explant (PDE) model that recapitulates the complexity of the clinical tissue microenvironment (Centenera et al, 2012), we targeted the rate-limiting enzyme in mitochondrial Fatty acid b-oxidation (FAO), carnitine palmitoyltransferase-1 (CPT-1), in cultured PDEs using the chemical inhibitor etomoxir
Previous research has largely focused on studying and targeting FA synthetic pathways in PCa. Major lipogenic enzymes such as ATP citrate lyase (ACLY), acetyl-CoA carboxylase (ACC) and fatty acid synthase (FASN) are all overexpressed in PCa compared to benign tissue (Wu et al, 2014; Rossi et al, 2003; Shurbaji et al, 1996)
Summary
Prostate cancer (PCa) is the most prevalent male cancer and the second leading cause of cancer deaths in men in Western societies (Bray et al, 2018). The development and FDA approval of agents that more effectively target androgen signaling, including enzalutamide (ENZ, Xtandi; an AR antagonist) (Tran et al, 2009; Cai and Balk, 2011; Rodrigues et al, 2014), has expanded the therapeutic options for CRPC. Even these approaches cannot durably control tumor growth and there is considerable variability in the nature and duration of responses between different patients (Tran et al, 2009; Scher et al, 2012; Davis et al, 2019). Alternative therapeutic strategies that enhance response to ADT, and thereby prevent or delay PCa progression to CRPC, are essential
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