二十二碳六烯酸通过抑制 Atg4B 来抑制自噬,从而提高了对去势抵抗性前列腺癌的疗效。

IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Archives of biochemistry and biophysics Pub Date : 2024-08-23 DOI:10.1016/j.abb.2024.110135
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引用次数: 0

摘要

癌症中的自噬诱导参与了癌症进展和抗癌药物耐药性的获得。因此,自噬被认为是癌症治疗的潜在靶点。在这项研究中,我们根据最近开发的一种 Atg4B 抑制剂 21f 的药理作用机制进行筛选,发现长链脂肪酸(LCFAs)对 Atg4B 有抑制作用,而 Atg4B 是自噬体形成所必需的。在这些脂肪酸中,多不饱和脂肪酸二十二碳六烯酸(DHA)对 Atg4B 的抑制活性最强。DHA 可抑制雄激素受体信号转导抑制剂(ARSI)诱导的 LNCaP 和 22Rv1 前列腺癌细胞的自噬,并显著增加细胞凋亡。此外,我们还通过建立对达罗他胺(一种新型 ARSI)产生抗性的达罗他胺抗性前列腺癌 22Rv1 (22Rv1/Dar)细胞,研究了 DHA 对 ARSI 抗性的影响。与亲代22Rv1细胞相比,22Rv1/Dar细胞的自噬水平较高。DHA能明显抑制Dar诱导的自噬,并通过线粒体功能障碍诱导细胞凋亡,从而使22Rv1/Dar细胞变得敏感。这些结果表明,补充 DHA 可改善前列腺癌的 ARSI 治疗。
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Docosahexaenoic acid enhances the treatment efficacy for castration-resistant prostate cancer by inhibiting autophagy through Atg4B inhibition

Autophagy induction in cancer is involved in cancer progression and the acquisition of resistance to anticancer agents. Therefore, autophagy is considered a potential therapeutic target in cancer therapy. In this study, we found that long-chain fatty acids (LCFAs) have inhibitory effects on Atg4B, which is essential for autophagosome formation, through screening based on the pharmacophore of 21f, a recently developed Atg4B inhibitor. Among these fatty acids, docosahexaenoic acid (DHA), a polyunsaturated fatty acid, exhibited the most potent Atg4B inhibitory activity. DHA inhibited autophagy induced by androgen receptor signaling inhibitors (ARSI) in LNCaP and 22Rv1 prostate cancer cells and significantly increased apoptotic cell death. Furthermore, we investigated the effect of DHA on resistance to ARSI by establishing darolutamide-resistant prostate cancer 22Rv1 (22Rv1/Dar) cells, which had developed resistance to darolutamide, a novel ARSI. At baseline, 22Rv1/Dar cells showed a higher autophagy level than parental 22Rv1 cells. DHA significantly suppressed Dar-induced autophagy and sensitized 22Rv1/Dar cells by inducing apoptotic cell death through mitochondrial dysfunction. These results suggest that DHA supplementation may improve prostate cancer therapy with ARSI.

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来源期刊
Archives of biochemistry and biophysics
Archives of biochemistry and biophysics 生物-生化与分子生物学
CiteScore
7.40
自引率
0.00%
发文量
245
审稿时长
26 days
期刊介绍: Archives of Biochemistry and Biophysics publishes quality original articles and reviews in the developing areas of biochemistry and biophysics. Research Areas Include: • Enzyme and protein structure, function, regulation. Folding, turnover, and post-translational processing • Biological oxidations, free radical reactions, redox signaling, oxygenases, P450 reactions • Signal transduction, receptors, membrane transport, intracellular signals. Cellular and integrated metabolism.
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