MICU1 drives glycolysis and chemoresistance in ovarian cancer

Prabir K Chakraborty,Priyabrata Mukherjee,Scott Mcmeekin,Min Zhang,Soumyajit Banerjee Mustafi,Kai Ding,Robert Mannel,Da Yang,Sounik Saha,Leonidas Tsiokas,Kathleen Moore,Vasyl Nesin,Xunhao Xiong,Rosemary Zuna,Shailendra Kumar Dhar Dwivedi,Muralidharan Jayaraman,Danny Dhanasekaran,Resham Bhattacharya

doi:10.1038/ncomms14634

Abstract

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.

Highlights

Cancer cells actively promote aerobic glycolysis to sustain their metabolic requirements through mechanisms not always clear
store-operated channels (SOC) are activated through a mechanism in which depletion of intracellular Ca2 þ stores leads to aggregation of Stromal interaction molecule 1 (STIM1), that is, the Ca2 þ sensor in endoplasmic reticulum (ER), and Orai[1], the membrane-bound Ca2 þ channel protein[11]
Since mitochondrial Ca2 þ uptake 1 (MICU1) is overexpressed both in OvCa cell lines and primary ovarian cancers and overexpression correlated with poor survival, we sought to determine the functional significance of MICU1 in OvCa growth and drug resistance

Summary

Introduction

Cancer cells actively promote aerobic glycolysis to sustain their metabolic requirements through mechanisms not always clear. Alterations in Ca2 þ signalling may not be a requirement for the initiation of cancer, the consequences of altered Ca2 þ transport in cancer cells may contribute to tumour progression and drug resistance[9] Characterizing such changes may help to identify new therapeutic targets. Recent reports suggest that in the absence of MICU1, the mitochondria become constitutively loaded with Ca2 þ , resulting in excessive ROS generation and sensitivity to apoptotic stress[15] In this context, our previous work has shown that small interfering RNA-mediated silencing of MICU1 sensitized OvCa cells to positively charged gold nanoparticles[18], suggesting for the first time a potential role of MICU1 in drug resistance. Our results purport possible therapeutic application of MICU1 targeting as an innovative way to normalize aberrant metabolism in cancer to improve poor prognosis

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Conclusion