elife-54166_Nassar ZD et al 2020_DECR1.pdf (6.39 MB)
Human decr1 is an androgen-repressed survival factor that regulates pufa oxidation to protect prostate tumor cells from ferroptosis
Version 2 2023-12-21, 01:37
Version 1 2021-08-13, 01:54
journal contributionposted on 2021-08-13, 01:54 authored by ZD Nassar, CY Mah, J Dehairs, Ingrid Burvenich, S Irani, MM Centenera, M Helm, RK Shrestha, M Moldovan, AS Don, J Holst, Andrew ScottAndrew Scott, LG Horvath, DJ Lynn, LA Selth, AJ Hoy, JV Swinnen, LM Butler
Fatty acid b-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 b-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.
National Health and Medical Research Council 1138648 Zeyad D NassarNational Health and Medical Research Council 1121057 Luke A SelthNational Health and Medical Research Council 1100626 Anthony S DonNational Health and Medical Research Council 1084178 Andrew M ScottProstate Cancer Foundation of Australia YI 1417 Zeyad D NassarCure Cancer Australia Foundation 1164798 Zeyad D NassarEMBL Australia Group Leader Award David J LynnUniversity of Sydney Robinson Fellowship Andrew J HoyFonds Wetenschappelijk Onderzoek Project Grants G.0841.15 and G.0C22.19N Johannes V SwinnenKU Leuven Project Grants C16/15/073 and C32/17/052 Johannes V SwinnenAustralian Research Council FT130101004 Lisa M ButlerCancer Council South Australia PRF1117 Lisa M ButlerMovember Foundation MRTA3 Lisa M ButlerFreemasons Foundation Centre for Men's Health, University of Adelaide Lisa M ButlerThe funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Pagination34p. (p. 1-34)
PublishereLife Sciences Publications
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Science & TechnologyLife Sciences & BiomedicineBiologyLife Sciences & Biomedicine - Other TopicsPOLYUNSATURATED FATTY-ACIDSRNA-SEQ ANALYSISEX-VIVO CULTUREREDUCTASE DEFICIENCYISOFORM DEFICIENCYPHYSICAL-ACTIVITYLIPID-METABOLISMBETA-OXIDATIONCANCER RISKPROGRESSIONCell Line, TumorHumansProstatic NeoplasmsOxidoreductases Acting on CH-CH Group DonorsFatty Acids, UnsaturatedOxidation-ReductionMaleFerroptosisandrogencancer biologyferroptosishumanlipid metabolismmouseprostate cancer