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MICU1 drives glycolysis and chemoresistance in ovarian cancer

Cancer cells actively promote aerobic glycolysis to sustain their metabolic requirements through mechanisms not always clear. Here, we demonstrate that the gatekeeper of mitochondrial Ca(2+) uptake, Mitochondrial Calcium Uptake 1 (MICU1/CBARA1) drives aerobic glycolysis in ovarian cancer. We show th...

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Autores principales: Chakraborty, Prabir K., Mustafi, Soumyajit Banerjee, Xiong, Xunhao, Dwivedi, Shailendra Kumar Dhar, Nesin, Vasyl, Saha, Sounik, Zhang, Min, Dhanasekaran, Danny, Jayaraman, Muralidharan, Mannel, Robert, Moore, Kathleen, McMeekin, Scott, Yang, Da, Zuna, Rosemary, Ding, Kai, Tsiokas, Leonidas, Bhattacharya, Resham, Mukherjee, Priyabrata
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5477507/
https://www.ncbi.nlm.nih.gov/pubmed/28530221
http://dx.doi.org/10.1038/ncomms14634
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author Chakraborty, Prabir K.
Mustafi, Soumyajit Banerjee
Xiong, Xunhao
Dwivedi, Shailendra Kumar Dhar
Nesin, Vasyl
Saha, Sounik
Zhang, Min
Dhanasekaran, Danny
Jayaraman, Muralidharan
Mannel, Robert
Moore, Kathleen
McMeekin, Scott
Yang, Da
Zuna, Rosemary
Ding, Kai
Tsiokas, Leonidas
Bhattacharya, Resham
Mukherjee, Priyabrata
author_facet Chakraborty, Prabir K.
Mustafi, Soumyajit Banerjee
Xiong, Xunhao
Dwivedi, Shailendra Kumar Dhar
Nesin, Vasyl
Saha, Sounik
Zhang, Min
Dhanasekaran, Danny
Jayaraman, Muralidharan
Mannel, Robert
Moore, Kathleen
McMeekin, Scott
Yang, Da
Zuna, Rosemary
Ding, Kai
Tsiokas, Leonidas
Bhattacharya, Resham
Mukherjee, Priyabrata
author_sort Chakraborty, Prabir K.
collection PubMed
description Cancer cells actively promote aerobic glycolysis to sustain their metabolic requirements through mechanisms not always clear. Here, we demonstrate that the gatekeeper of mitochondrial Ca(2+) 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.
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spelling pubmed-54775072017-07-03 MICU1 drives glycolysis and chemoresistance in ovarian cancer Chakraborty, Prabir K. Mustafi, Soumyajit Banerjee Xiong, Xunhao Dwivedi, Shailendra Kumar Dhar Nesin, Vasyl Saha, Sounik Zhang, Min Dhanasekaran, Danny Jayaraman, Muralidharan Mannel, Robert Moore, Kathleen McMeekin, Scott Yang, Da Zuna, Rosemary Ding, Kai Tsiokas, Leonidas Bhattacharya, Resham Mukherjee, Priyabrata Nat Commun Article Cancer cells actively promote aerobic glycolysis to sustain their metabolic requirements through mechanisms not always clear. Here, we demonstrate that the gatekeeper of mitochondrial Ca(2+) 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. Nature Publishing Group 2017-05-22 /pmc/articles/PMC5477507/ /pubmed/28530221 http://dx.doi.org/10.1038/ncomms14634 Text en Copyright © 2017, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Chakraborty, Prabir K.
Mustafi, Soumyajit Banerjee
Xiong, Xunhao
Dwivedi, Shailendra Kumar Dhar
Nesin, Vasyl
Saha, Sounik
Zhang, Min
Dhanasekaran, Danny
Jayaraman, Muralidharan
Mannel, Robert
Moore, Kathleen
McMeekin, Scott
Yang, Da
Zuna, Rosemary
Ding, Kai
Tsiokas, Leonidas
Bhattacharya, Resham
Mukherjee, Priyabrata
MICU1 drives glycolysis and chemoresistance in ovarian cancer
title MICU1 drives glycolysis and chemoresistance in ovarian cancer
title_full MICU1 drives glycolysis and chemoresistance in ovarian cancer
title_fullStr MICU1 drives glycolysis and chemoresistance in ovarian cancer
title_full_unstemmed MICU1 drives glycolysis and chemoresistance in ovarian cancer
title_short MICU1 drives glycolysis and chemoresistance in ovarian cancer
title_sort micu1 drives glycolysis and chemoresistance in ovarian cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5477507/
https://www.ncbi.nlm.nih.gov/pubmed/28530221
http://dx.doi.org/10.1038/ncomms14634
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