TY - JOUR
T1 - The epithelial to mesenchymal transition promotes glutamine independence by suppressing GLS2 expression
AU - Ramirez-Peña, Esmeralda
AU - Arnold, James
AU - Shivakumar, Vinita
AU - Joseph, Robiya
AU - Vijay, Geraldine Vidhya
AU - Hollander, Petra den
AU - Bhangre, Neeraja
AU - Allegakoen, Paul
AU - Prasad, Rishika
AU - Conley, Zachary
AU - Matés, José M.
AU - Márquez, Javier
AU - Chang, Jeffrey T.
AU - Vasaikar, Suhas
AU - Soundararajan, Rama
AU - Sreekumar, Arun
AU - Mani, Sendurai A.
N1 - Funding Information:
Funding: This work was supported by the National Science Foundation (PHY-1605817) and National Institute of Health and National Cancer Institute (2R01CA155243). J.M.M. and J.M. are supported by SAF2015-64501-R and RTI2018-096866-B-I00 from the Spanish Ministry of Science, Innovation and Universities.
Funding Information:
This work was supported by the National Science Foundation (PHY-1605817) and National Institute of Health and National Cancer Institute (2R01CA155243). J.M.M. and J.M. are supported by SAF2015-64501-R and RTI2018-096866-B-I00 from the Spanish Ministry of Science, Innovation and Universities.
Funding Information:
National Cancer Institute, Cancer Prevention Fellowship Program, Division of Cancer Prevention, Bethesda, MD 20892, USA; esmeralda.ramirez-pena@nih.gov Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, TX 77030, USA; j.arnold221@gmail.com (J.A.); Arun.Sreekumar@bcm.edu (A.S.) Wiess School of Natural Sciences, Rice University, Houston, TX 77005, USA; vs28@rice.edu Department of Translational Molecular Pathology, MD Anderson Cancer Center, Houston, TX 77030, USA; RJoseph7@mdanderson.org (R.J.); PDHollander@mdanderson.org (P.d.H.); rprasad3@mdanderson.org (R.P.); SVVasaikar@mdanderson.org (S.V.); RSoundararajan@mdanderson.org (R.S.) Department of Immunology, Mayo Clinic, Jacksonville, FL 32224, USA; Raja.geraldine@mayo.edu Department of Fibrosis Biology, Gilead Sciences, Foster City, CA 94404, USA; neeraja.bhangre@gilead.com Department of Medicine, University of California-San Francisco, San Francisco, CA 94143, USA; paul.allegakoen@ucsf.edu Center for Science Outreach, Department of Teaching and Learning, Vanderbilt University, Nashville, TN 37235, USA; zachary.c.conley@vanderbilt.edu Canceromics Lab, Department of Molecular Biology and Biochemistry, University of Málaga and Instituto de Investigación Biomedica de Málaga (IBIMA), 29071 Málaga, Spain; jmates@uma.es (J.M.M.); marquez@uma.es (J.M.) 10 Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, TX 77030, USA; Jeffrey.T.Chang@uth.tmc.edu
Publisher Copyright:
© 2019 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2019/10
Y1 - 2019/10
N2 - 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.
AB - 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.
KW - Breast cancer
KW - EMT
KW - FOXC2
KW - GLS2
KW - Glutamine metabolism
UR - http://www.scopus.com/inward/record.url?scp=85075593545&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85075593545&partnerID=8YFLogxK
U2 - 10.3390/cancers11101610
DO - 10.3390/cancers11101610
M3 - Article
C2 - 31652551
AN - SCOPUS:85075593545
SN - 2072-6694
VL - 11
JO - Cancers
JF - Cancers
IS - 10
M1 - 1610
ER -