Dual inhibition of glycolysis and glutaminolysis as a therapeutic strategy in the treatment of ovarian cancer
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Li Sun1,3,*, Yajie Yin1,2,3,*, Leslie H. Clark3, Wenchuan Sun3, Stephanie A. Sullivan3, Arthur-Quan Tran3, Jianjun Han4, Lu Zhang1, Hui Guo1, Esther Madugu3, Tommy Pan3, Amanda L. Jackson5, Joshua Kilgore6, Hannah M. Jones3, Timothy P. Gilliam3, Chunxiao Zhou3,7 and Victoria L. Bae-Jump3,7
1Department of Gynecologic Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan, Shandong Province, People’s Republic of China
2School of Medicine and Life Sciences, University of Jinan, Shandong Academy of Medical Sciences, Jinan, Shandong Province, People’s Republic of China
3Division of Gynecologic Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
4Department of Surgical Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan, Shandong Province, People’s Republic of China
5Division of Gynecologic Oncology, University of Cincinnati, Cincinnati, OH, USA
6Houston Methodist Gynecologic Oncology Associates, Houston, TX, USA
7Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
*These authors have contributed equally to this work
Victoria L. Bae-Jump, email: [email protected]
Chunxiao Zhou, email: [email protected]
Keywords: glycolysis, glutaminolysis, ovarian cancer, AMPK/mTOR
Received: April 19, 2017 Accepted: June 04, 2017 Published: June 29, 2017
Cancer cell metabolism is required to support the biosynthetic demands of cell growth and cell division, and to maintain reduction oxidaton (redox) homeostasis. This study was designed to test the effects of glucose and glutamine on ovarian cancer cell growth and explore the inter-relationship between glycolysis and glutaminolysis. The SKOV3, IGROV-1 and Hey ovarian cancer cell lines were assayed for glucose, pyruvate and glutamine dependence by analyzing cytotoxicity, cell cycle progression, apoptosis and ATP production. As determined by MTT assay, glucose stimulated cell growth while the combination of glucose, glutamine and pyruvate resulted in the greatest stimulation of cell proliferation. Furthermore, 2-deoxy-glucose (2-DG) and 3-bromopyruvate (3-BP) induced apoptosis, caused G1 phase cell cycle arrest and reduced glycolytic activity. Moreover, 2-DG in combination with a low dose of aminooxyacetate (AOA) synergistically increased the sensitivity to 2-DG in the inhibition of cell growth in the ovarian cancer cell lines. These studies suggest that dual inhibition of glycolysis and glutaminolysis may be a promising therapeutic strategy for the treatment of ovarian cancer.
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