Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.
Department of Obstetrics and Gynecology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.
Nat Commun. 2017 May 22;8:14634. doi: 10.1038/ncomms14634.
Cancer cells actively promote aerobic glycolysis to sustain their metabolic requirements through mechanisms not always clear. Here, we demonstrate that the gatekeeper of mitochondrial Ca uptake, Mitochondrial Calcium Uptake 1 (MICU1/CBARA1) drives aerobic glycolysis in ovarian cancer. We show that MICU1 is overexpressed in a panel of ovarian cancer cell lines and that MICU1 overexpression correlates with poor overall survival (OS). Silencing MICU1 in vitro increases oxygen consumption, decreases lactate production, inhibits clonal growth, migration and invasion of ovarian cancer cells, whereas silencing in vivo inhibits tumour growth, increases cisplatin efficacy and OS. Mechanistically, silencing MICU1 activates pyruvate dehydrogenase (PDH) by stimulating the PDPhosphatase-phosphoPDH-PDH axis. Forced-expression of MICU1 in normal cells phenocopies the metabolic aberrations of malignant cells. Consistent with the in vitro and in vivo findings we observe a significant correlation between MICU1 and pPDH (inactive form of PDH) expression with poor prognosis. Thus, MICU1 could serve as an important therapeutic target to normalize metabolic aberrations responsible for poor prognosis in ovarian cancer.
癌细胞通过机制主动促进有氧糖酵解，以维持其代谢需求，但这些机制并不总是清楚。在这里，我们证明了线粒体钙摄取的守门员，线粒体钙摄取 1 （MICU1/CBARA1），在卵巢癌中驱动有氧糖酵解。我们表明，MICU1 在一系列卵巢癌细胞系中过表达，并且 MICU1 的过表达与整体生存率（OS）差相关。体外沉默 MICU1 会增加耗氧量，减少乳酸生成，抑制卵巢癌细胞的克隆生长、迁移和侵袭，而体内沉默则会抑制肿瘤生长，增加顺铂的疗效和 OS。在机制上，沉默 MICU1 通过刺激 PDH 磷酸酶-磷酸化 PDH-PDH 轴来激活丙酮酸脱氢酶（PDH）。在正常细胞中强制表达 MICU1 可模拟恶性细胞的代谢异常。与体外和体内的研究结果一致，我们观察到 MICU1 与 pPDH（PDH 的无活性形式）表达之间存在显著相关性，与预后不良相关。因此，MICU1 可以作为一个重要的治疗靶点，纠正导致卵巢癌预后不良的代谢异常。
