人类 DECR1 是一种雄激素受抑制的生存因子，可调节多不饱和脂肪酸氧化，以保护前列腺肿瘤细胞免受铁死亡。
Human DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumor cells from ferroptosis.
机构信息
University of Adelaide Medical School and Freemasons Foundation Centre for Men's Health, University of Adelaide, Adelaide, Australia.
South Australian Health and Medical Research Institute, Adelaide, Australia.
出版信息
Elife. 2020 Jul 20;9:e54166. doi: 10.7554/eLife.54166.
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 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. 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.
脂肪酸β-氧化（FAO）是人类前列腺癌（PCa）的主要生物能量途径，也是一种有前途的新型治疗弱点。在这里，我们证明了靶向 FAO 在体外培养的临床前列腺肿瘤中的治疗效果，并鉴定出编码多不饱和脂肪酸（PUFAs）氧化限速酶的 ，在 PCa 组织中强烈过表达，并与较短的无复发生存时间相关。 是一个负调控的雄激素受体（AR）靶基因，因此，可能促进 PCa 细胞的存活和对 AR 靶向治疗的耐药性。DECR1 敲低选择性地抑制了 PUFAs 的β-氧化，抑制了包括耐药株在内的 PCa 细胞的增殖和迁移，并抑制了小鼠异种移植模型中的肿瘤细胞增殖和转移。在机制上，DECR1 的靶向作用导致 PUFAs 的细胞积累，增强了线粒体氧化应激和脂质过氧化，并诱导了铁死亡。这些发现表明，通过 DECR1 进行 PUFA 氧化是 FAO 的一个未被探索的方面，它促进了 PCa 细胞的存活。
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