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Nat Commun. 2017 May 22;8:14634. doi: 10.1038/ncomms14634.

MICU1 drives glycolysis and chemoresistance in ovarian cancer.

Author information

1
Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.
2
Department of Obstetrics and Gynecology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.
3
Department of Cell Biology, The University of Oklahoma Health Sciences Center, Oklahoma 73104, USA.
4
Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania 15261, USA.
5
Peggy and Charles Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.
6
College of Public Health, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.

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.

PMID:
28530221
PMCID:
PMC5477507
DOI:
10.1038/ncomms14634
[Indexed for MEDLINE]
Free PMC Article

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