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© 2020, Nassar et al. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

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.

Details

Title
Human DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumor cells from ferroptosis
Author
Nassar, Zeyad D; Mah Chui Yan; Dehairs Jonas; Burvenich Ingrid JG; Irani Swati; Centenera, Margaret M; Helm Madison; Shrestha, Raj K; Moldovan, Max; Don, Anthony S; Holst, Jeff; Scott, Andrew M; Horvath, Lisa G; Lynn, David J; Selth Luke A; Hoy, Andrew J; Swinnen, Johannes V; Butler, Lisa M
University/institution
U.S. National Institutes of Health/National Library of Medicine
Publication year
2020
Publication date
2020
Publisher
eLife Sciences Publications Ltd.
e-ISSN
2050084X
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2429407751
Copyright
© 2020, Nassar et al. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.