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MICU1 drives glycolysis and chemoresistance in ovarian cancer

Author

Listed:
  • 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
    Peggy and Charles Stephenson Cancer Center, 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
    Peggy and Charles Stephenson Cancer Center, The University of Oklahoma Health Sciences Center)

  • Kathleen Moore

    (The University of Oklahoma Health Sciences Center
    Peggy and Charles Stephenson Cancer Center, The University of Oklahoma Health Sciences Center)

  • Scott McMeekin

    (The University of Oklahoma Health Sciences Center
    Peggy and Charles Stephenson Cancer Center, The University of Oklahoma Health Sciences Center)

  • Da Yang

    (University of Pittsburgh School of Pharmacy)

  • Rosemary Zuna

    (The University of Oklahoma Health Sciences Center
    Peggy and Charles Stephenson Cancer Center, 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
    Peggy and Charles Stephenson Cancer Center, The University of Oklahoma Health Sciences Center)

  • Priyabrata Mukherjee

    (The University of Oklahoma Health Sciences Center
    Peggy and Charles Stephenson Cancer Center, The University of Oklahoma Health Sciences Center)

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.

Suggested Citation

  • Prabir K. Chakraborty & Soumyajit Banerjee Mustafi & Xunhao Xiong & Shailendra Kumar Dhar Dwivedi & Vasyl Nesin & Sounik Saha & Min Zhang & Danny Dhanasekaran & Muralidharan Jayaraman & Robert Mannel , 2017. "MICU1 drives glycolysis and chemoresistance in ovarian cancer," Nature Communications, Nature, vol. 8(1), pages 1-16, August.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14634
    DOI: 10.1038/ncomms14634
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