MYC 是雄激素受体抑制诱导前列腺癌代谢需求的调节因子。
MYC is a regulator of androgen receptor inhibition-induced metabolic requirements in prostate cancer.
机构信息
Molecular Biology Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
出版信息
Cell Rep. 2023 Oct 31;42(10):113221. doi: 10.1016/j.celrep.2023.113221. Epub 2023 Oct 9.
Advanced prostate cancers are treated with therapies targeting the androgen receptor (AR) signaling pathway. While many tumors initially respond to AR inhibition, nearly all develop resistance. It is critical to understand how prostate tumor cells respond to AR inhibition in order to exploit therapy-induced phenotypes prior to the outgrowth of treatment-resistant disease. Here, we comprehensively characterize the effects of AR blockade on prostate cancer metabolism using transcriptomics, metabolomics, and bioenergetics approaches. The metabolic response to AR inhibition is defined by reduced glycolysis, robust elongation of mitochondria, and increased reliance on mitochondrial oxidative metabolism. We establish DRP1 activity and MYC signaling as mediators of AR-blockade-induced metabolic phenotypes. Rescuing DRP1 phosphorylation after AR inhibition restores mitochondrial fission, while rescuing MYC restores glycolytic activity and prevents sensitivity to complex I inhibition. Our study provides insight into the regulation of treatment-induced metabolic phenotypes and vulnerabilities in prostate cancer.
晚期前列腺癌采用靶向雄激素受体 (AR) 信号通路的治疗方法进行治疗。虽然许多肿瘤最初对 AR 抑制有反应，但几乎所有肿瘤最终都会产生耐药性。了解前列腺肿瘤细胞对 AR 抑制的反应对于在治疗耐药性疾病出现之前利用治疗诱导的表型至关重要。在这里，我们使用转录组学、代谢组学和生物能量学方法全面描述了 AR 阻断对前列腺癌代谢的影响。AR 抑制的代谢反应表现为糖酵解减少、线粒体伸长增强以及对线粒体氧化代谢的依赖性增加。我们确定 DRP1 活性和 MYC 信号作为 AR 阻断诱导的代谢表型的介质。在 AR 抑制后恢复 DRP1 磷酸化可恢复线粒体分裂，而恢复 MYC 可恢复糖酵解活性并防止对复合物 I 抑制的敏感性。我们的研究为治疗诱导的代谢表型和前列腺癌的脆弱性的调控提供了深入的了解。
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