Abstract 237: DECR1: The rate limiting enzyme of polyunsaturated fatty acid metabolism and a novel therapeutic target in prostate cancer

Abstract

Abstract Introduction: Fatty acid oxidation (FAO) is the dominant bioenergetic pathway in prostate cancer (PCa). Previous studies have demonstrated efficacy in targeting key FAO enzymes using in vitro and in vivo models of PCa. However, clinical evidence supporting FAO targeting in PCa is lacking. A recent study reported that FAO is upregulated in PCa cells and is essential for cell viability. Here, we demonstrated therapeutic efficacy of targeting FAO in clinical prostate tumors and identified DECR1 as a potential FAO-related survival factor. Methods and Results: To examine the therapeutic efficacy of targeting FAO in a more clinically-relevant setting, patient-derived prostate explants (PDE) were treated with etomoxir (FAO inhibitor). Results showed significant inhibition of cell proliferation (evaluated using Ki67 immunohistochemistry staining) in drug-treated PDE by a mean of 48% (n=13, p<0.05). To identify key targets of FAO in PCa, a meta-analysis was performed using four clinical RNA-sequencing datasets comprising of malignant and matched normal PCa patient tissues. DECR1 – the rate limiting enzyme of polyunsaturated fatty acid (PUFA) oxidation was identified as a robustly overexpressed FAO gene in PCa tissues; its expression is significantly associated with shorter biochemical recurrence-free survival and overall PCa patient survival. Consistent with the vital role of DECR1 in PUFA oxidation, knockdown of DECR1 impaired the cell's capacity to metabolize PUFAs; furthermore, FAO inhibition via DECR1 knockdown is specific to PUFA oxidation. Notably, DECR1 knockdown significantly inhibited PCa cell proliferation, migration, and invasion, and significantly reduced cellular proliferation in tumors. Mechanistically, DECR1 knockdown results in the induction of lipid peroxidation and cell death via ferroptosis in PCa cells. In contrast, overexpression of DECR1 significantly decreased mitochondrial oxidative stress and reduced levels of malondialdehyde. Treatment of PCa cells with ferrostatin successfully rescued PCa cells from death by DECR1 inhibition. Taken together, these data suggest that overexpression of DECR1 may offer PCa cells a survival advantage by protecting the cells from ferroptosis. Conclusion: This study demonstrated for the first time clinically-relevant evidence that targeting FAO is efficacious and provides evidence for the importance of FAO, and specifically PUFA oxidation, in PCa progression. Importantly, this study identified DECR1 as a promising and novel therapeutic target for PCa. Citation Format: Chui Yan Mah, Zeyad D. Nassar, Ingrid J. Burvenich, Swati Irani, Margaret M. Centenera, Max Moldovan, David J. Lynn, Andrew J. Hoy, Johannes V. Swinnen, Lisa M. Butler. DECR1: The rate limiting enzyme of polyunsaturated fatty acid metabolism and a novel therapeutic target in prostate cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 237.