Human DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to Protect prostate tumor cells from ferroptosis
Human DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to Protect prostate tumor cells from ferroptosis
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DOI：
10.7554/elife.54166
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发表时间：
2020-07-20
期刊：
影响因子：
7.7
通讯作者：
Butler, Lisa M.
中科院分区：
文献类型：
--
作者：
Nassar, Zeyad D.;Mah, Chui Yan;Butler, Lisa M.
脂肪酸β-氧化（FAO）是人类前列腺癌（PCa）的主要生物能量途径，是一种有前途的新的治疗弱点。在这里，我们证明了在离体培养的临床前列腺肿瘤中靶向FAO的治疗效果，并鉴定了DECR 1，其编码多不饱和脂肪酸（PUFA）氧化的限速酶，在PCa组织中强烈过表达，并与较短的无复发生存期相关。DECR 1是一种负调节的雄激素受体（AR）靶基因，因此，可能会促进PCa细胞存活和对AR靶向治疗的抗性。DECR 1敲低选择性地抑制PUFA的13氧化，抑制PCa细胞的增殖和迁移，包括治疗抗性系，并抑制小鼠异种移植模型中的肿瘤细胞增殖和转移。机制上，靶向DECR 1导致PUFA的细胞积累，增强线粒体氧化应激和脂质过氧化，并诱导铁凋亡。这些发现暗示通过DECR 1的PUFA氧化是FAO促进PCa细胞存活的未探索方面。
Fatty acid beta-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 13oxidation 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.