MICU1 drives glycolysis and chemoresistance in ovarian cancer.
MICU1 drives glycolysis and chemoresistance in ovarian cancer.
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DOI：
10.1038/ncomms14634
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发表时间：
2017-05-22
影响因子：
16.6
通讯作者：
Mukherjee P
中科院分区：
文献类型：
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作者：
Chakraborty PK;Mustafi SB;Xiong X;Dwivedi SKD;Nesin V;Saha S;Zhang M;Dhanasekaran D;Jayaraman M;Mannel R;Moore K;McMeekin S;Yang D;Zuna R;Ding K;Tsiokas L;Bhattacharya R;Mukherjee P
癌细胞积极促进有氧糖酵解，以维持其代谢需求，其机制并不总是很清楚。在这里，我们证明了线粒体钙摄取的守门人线粒体钙摄取1(MICU1/CBARA1)在卵巢癌中驱动有氧糖酵解。我们发现MICU1在一组卵巢癌细胞系中过度表达，并且MICU1过度表达与较差的总体生存率(OS)相关。在体外沉默MICU1可以增加氧气消耗，减少乳酸的产生，抑制卵巢癌细胞的克隆生长、迁移和侵袭，而体内沉默则抑制肿瘤生长，增加顺铂疗效和OS。机制上，沉默MICU1通过刺激丙酮酸脱氢酶(PDH)-磷酸-磷酸脱氢酶(PDH-PDH)轴来激活PDH。MICU1在正常细胞中的强制表达复制了肿瘤细胞的代谢异常。与体外和体内的研究结果一致，我们观察到MICU1与pPDH(非活动性PDH)的表达显著相关，预后不良。因此，MICU1可以作为一个重要的治疗靶点，使导致卵巢癌预后不良的代谢异常正常化。线粒体单一转运体MICU1调节线粒体钙摄取。在这里，作者表明MICU1在卵巢癌中上调，并通过钙离子介导的丙酮酸脱氢酶活性的调节而对顺铂诱导的细胞凋亡产生抵抗，从而导致糖酵解增加。
Cancer cells actively promote aerobic glycolysis to sustain their metabolic requirements through mechanisms not always clear. Here, we demonstrate that the gatekeeper of mitochondrial Ca2+ 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. The mitochondrial uniporter MICU1 regulates mitochondrial Ca2+ uptake. Here, the authors show that MICU1 is upregulated in ovarian cancer and confers resistance to cisplatin-induced apoptosis through a Ca2+-mediated regulation of pyruvate dehydrogenase activity that results in increased glycolysis.