MICU1 drives glycolysis and chemoresistance in ovarian cancer

Prabir K. Chakraborty, Soumyajit Banerjee Mustafi, Xunhao Xiong, Shailendra Kumar Dhar Dwivedi, Vasyl Nesin, Sounik Saha, Min Zhang, Danny Dhanasekaran, Muralidharan Jayaraman, Robert Mannel, Kathleen Moore, Scott McMeekin, Da Yang, Rosemary Zuna, Kai Ding, Leonidas Tsiokas, Resham Bhattacharya and Priyabrata Mukherjee ()
Additional contact information
Prabir K. Chakraborty: The University of Oklahoma Health Sciences Center
Soumyajit Banerjee Mustafi: The University of Oklahoma Health Sciences Center
Xunhao Xiong: The University of Oklahoma Health Sciences Center
Shailendra Kumar Dhar Dwivedi: The University of Oklahoma Health Sciences Center
Vasyl Nesin: The University of Oklahoma Health Sciences Center
Sounik Saha: The University of Oklahoma Health Sciences Center
Min Zhang: University of Pittsburgh School of Pharmacy
Danny Dhanasekaran: The University of Oklahoma Health Sciences Center
Muralidharan Jayaraman: The University of Oklahoma Health Sciences Center
Robert Mannel: The University of Oklahoma Health Sciences Center
Kathleen Moore: The University of Oklahoma Health Sciences Center
Scott McMeekin: The University of Oklahoma Health Sciences Center
Da Yang: University of Pittsburgh School of Pharmacy
Rosemary Zuna: The University of Oklahoma Health Sciences Center
Kai Ding: College of Public Health, The University of Oklahoma Health Sciences Center
Leonidas Tsiokas: The University of Oklahoma Health Sciences Center
Resham Bhattacharya: The University of Oklahoma Health Sciences Center
Priyabrata Mukherjee: The University of Oklahoma Health Sciences Center

Nature Communications, 2017, vol. 8, issue 1, 1-16

Abstract: 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.

Date: 2017
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14634

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DOI: 10.1038/ncomms14634

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