MYC 和 MCL1 通过调节线粒体氧化磷酸化协同促进化疗耐药的乳腺癌干细胞。
MYC and MCL1 Cooperatively Promote Chemotherapy-Resistant Breast Cancer Stem Cells via Regulation of Mitochondrial Oxidative Phosphorylation.
机构信息
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Department of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
出版信息
Cell Metab. 2017 Oct 3;26(4):633-647.e7. doi: 10.1016/j.cmet.2017.09.009.
Most patients with advanced triple-negative breast cancer (TNBC) develop drug resistance. MYC and MCL1 are frequently co-amplified in drug-resistant TNBC after neoadjuvant chemotherapy. Herein, we demonstrate that MYC and MCL1 cooperate in the maintenance of chemotherapy-resistant cancer stem cells (CSCs) in TNBC. MYC and MCL1 increased mitochondrial oxidative phosphorylation (mtOXPHOS) and the generation of reactive oxygen species (ROS), processes involved in maintenance of CSCs. A mutant of MCL1 that cannot localize in mitochondria reduced mtOXPHOS, ROS levels, and drug-resistant CSCs without affecting the anti-apoptotic function of MCL1. Increased levels of ROS, a by-product of activated mtOXPHOS, led to the accumulation of HIF-1α. Pharmacological inhibition of HIF-1α attenuated CSC enrichment and tumor initiation in vivo. These data suggest that (1) MYC and MCL1 confer resistance to chemotherapy by expanding CSCs via mtOXPHOS and (2) targeting mitochondrial respiration and HIF-1α may reverse chemotherapy resistance in TNBC.
大多数晚期三阴性乳腺癌（TNBC）患者会产生耐药性。新辅助化疗后，耐药性 TNBC 中经常同时扩增 MYC 和 MCL1。在此，我们证明 MYC 和 MCL1 在维持 TNBC 化疗耐药性癌症干细胞（CSC）中起协同作用。MYC 和 MCL1 增加线粒体氧化磷酸化（mtOXPHOS）和活性氧（ROS）的产生，这些过程参与维持 CSC。一种不能定位于线粒体的 MCL1 突变体可减少 mtOXPHOS、ROS 水平和耐药性 CSC，而不影响 MCL1 的抗凋亡功能。激活的 mtOXPHOS 的副产物 ROS 水平升高导致 HIF-1α 的积累。HIF-1α 的药理学抑制减弱了体内 CSC 富集和肿瘤起始。这些数据表明：（1）通过 mtOXPHOS 扩增 CSC，MYC 和 MCL1 赋予对化疗的耐药性；（2）靶向线粒体呼吸和 HIF-1α 可能逆转 TNBC 的化疗耐药性。
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