Mitochondrial pyruvate carrier function determines cell stemness and metabolic reprogramming in cancer cells
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Xiaoli Li1,2,*, Gaoyang Han3,*, Xiaoran Li2, Quancheng Kan4, Zhirui Fan1, Yaqing Li1,2, Yasai Ji1, Jing Zhao1, Mingzhi Zhang1, Mantas Grigalavicius2, Viktor Berge5, Mariusz Adam Goscinski6, Jahn M. Nesland2 and Zhenhe Suo1,2
1Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, 450000, China
2Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, 0379, Norway
3Department of Thoracic Surgery, The First Affiliated Hospital of Xinxiang Medical University, Weihui City, Henan Province, 453000, China
4Department of Clinical Pharmacology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, 450000, China
5Department of Urology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, 0379, Norway
6Department of Surgery, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, 0379, Norway
*These authors have contributed equally to this work
Zhenhe Suo, email: [email protected], [email protected]
Keywords: MPC, OXPHOS, TCA, glycolysis, stem cell
Received: November 09, 2016 Accepted: May 05, 2017 Published: May 25, 2017
One of the remarkable features of cancer cells is aerobic glycolysis, a phenomenon known as the “Warburg Effect”, in which cells rely preferentially on glycolysis instead of oxidative phosphorylation (OXPHOS) as the main energy source even in the presence of high oxygen tension. Cells with dysfunctional mitochondria are unable to generate sufficient ATP from mitochondrial OXPHOS, and then are forced to rely on glycolysis for ATP generation. Here we report our results in a prostate cancer cell line in which the mitochondrial pyruvate carrier 1 (MPC1) gene was knockout. It was discovered that the MPC1 gene knockout cells revealed a metabolism reprogramming to aerobic glycolysis with reduced ATP production, and the cells became more migratory and resistant to both chemotherapy and radiotherapy. In addition, the MPC1 knockout cells expressed significantly higher levels of the stemness markers Nanog, Hif1α, Notch1, CD44 and ALDH. To further verify the correlation of MPC gene function and cell stemness/metabolic reprogramming, MPC inhibitor UK5099 was applied in two ovarian cancer cell lines and similar results were obtained. Taken together, our results reveal that functional MPC may determine the fate of metabolic program and the stemness status of cancer cells in vitro.
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