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Article

The Epithelial to Mesenchymal Transition Promotes Glutamine Independence by Suppressing GLS2 Expression

1
National Cancer Institute, Cancer Prevention Fellowship Program, Division of Cancer Prevention, Bethesda, MD 20892, USA
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Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, TX 77030, USA
3
Wiess School of Natural Sciences, Rice University, Houston, TX 77005, USA
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Department of Translational Molecular Pathology, MD Anderson Cancer Center, Houston, TX 77030, USA
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Department of Immunology, Mayo Clinic, Jacksonville, FL 32224, USA
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Department of Fibrosis Biology, Gilead Sciences, Foster City, CA 94404, USA
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Department of Medicine, University of California-San Francisco, San Francisco, CA 94143, USA
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Center for Science Outreach, Department of Teaching and Learning, Vanderbilt University, Nashville, TN 37235, USA
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Canceromics Lab, Department of Molecular Biology and Biochemistry, University of Málaga and Instituto de Investigación Biomedica de Málaga (IBIMA), 29071 Málaga, Spain
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Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, TX 77030, USA
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(10), 1610; https://doi.org/10.3390/cancers11101610
Received: 8 September 2019 / Revised: 5 October 2019 / Accepted: 18 October 2019 / Published: 22 October 2019
Identifying bioenergetics that facilitate the epithelial to mesenchymal transition (EMT) in breast cancer cells may uncover targets to treat incurable metastatic disease. Metastasis is the number one cause of cancer-related deaths; therefore, it is urgent to identify new treatment strategies to prevent the initiation of metastasis. To characterize the bioenergetics of EMT, we compared metabolic activities and gene expression in cells induced to differentiate into the mesenchymal state with their epithelial counterparts. We found that levels of GLS2, which encodes a glutaminase, are inversely associated with EMT. GLS2 down-regulation was correlated with reduced mitochondrial activity and glutamine independence even in low-glucose conditions. Restoration of GLS2 expression in GLS2-negative breast cancer cells rescued mitochondrial activity, enhanced glutamine utilization, and inhibited stem-cell properties. Additionally, inhibition of expression of the transcription factor FOXC2, a critical regulator of EMT in GLS2-negative cells, restored GLS2 expression and glutamine utilization. Furthermore, in breast cancer patients, high GLS2 expression is associated with improved survival. These findings suggest that epithelial cancer cells rely on glutamine and that cells induced to undergo EMT become glutamine independent. Moreover, the inhibition of EMT leads to a GLS2-directed metabolic shift in mesenchymal cancer cells, which may make these cells susceptible to chemotherapies. View Full-Text
Keywords: GLS2; EMT; glutamine metabolism; breast cancer; FOXC2 GLS2; EMT; glutamine metabolism; breast cancer; FOXC2
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MDPI and ACS Style

Ramirez-Peña, E.; Arnold, J.; Shivakumar, V.; Joseph, R.; Vidhya Vijay, G.; den Hollander, P.; Bhangre, N.; Allegakoen, P.; Prasad, R.; Conley, Z.; Matés, J.M.; Márquez, J.; Chang, J.T.; Vasaikar, S.; Soundararajan, R.; Sreekumar, A.; Mani, S.A. The Epithelial to Mesenchymal Transition Promotes Glutamine Independence by Suppressing GLS2 Expression. Cancers 2019, 11, 1610. https://doi.org/10.3390/cancers11101610

AMA Style

Ramirez-Peña E, Arnold J, Shivakumar V, Joseph R, Vidhya Vijay G, den Hollander P, Bhangre N, Allegakoen P, Prasad R, Conley Z, Matés JM, Márquez J, Chang JT, Vasaikar S, Soundararajan R, Sreekumar A, Mani SA. The Epithelial to Mesenchymal Transition Promotes Glutamine Independence by Suppressing GLS2 Expression. Cancers. 2019; 11(10):1610. https://doi.org/10.3390/cancers11101610

Chicago/Turabian Style

Ramirez-Peña, Esmeralda, James Arnold, Vinita Shivakumar, Robiya Joseph, Geraldine Vidhya Vijay, Petra den Hollander, Neeraja Bhangre, Paul Allegakoen, Rishika Prasad, Zachary Conley, José M. Matés, Javier Márquez, Jeffrey T. Chang, Suhas Vasaikar, Rama Soundararajan, Arun Sreekumar, and Sendurai A. Mani. 2019. "The Epithelial to Mesenchymal Transition Promotes Glutamine Independence by Suppressing GLS2 Expression" Cancers 11, no. 10: 1610. https://doi.org/10.3390/cancers11101610

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