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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

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posted on 13.08.2021, 01:54 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.

Funding

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.

History

Publication Date

01/01/2020

Journal

eLife

Volume

9

Article Number

e54166

Pagination

34p. (p. 1-34)

Publisher

eLife Sciences Publications

ISSN

2050-084X

Rights Statement

The Author reserves all moral rights over the deposited text and must be credited if any re-use occurs. Documents deposited in OPAL are the Open Access versions of outputs published elsewhere. Changes resulting from the publishing process may therefore not be reflected in this document. The final published version may be obtained via the publisher’s DOI. Please note that additional copyright and access restrictions may apply to the published version.