RT Journal Article
T1 The Epithelial to Mesenchymal Transition Promotes Glutamine Independence by Suppressing GLS2 Expression.
A1 Ramirez-Peña, Esmeralda
A1 Arnold, James
A1 Shivakumar, Vinita
A1 Joseph, Robiya
A1 Vidhya Vijay, Geraldine
A1 den Hollander, Petra
A1 Bhangre, Neeraja
A1 Allegakoen, Paul
A1 Prasad, Rishika
A1 Conley, Zachary
A1 Matés, José M
A1 Márquez, Javier
A1 Chang, Jeffrey T
A1 Vasaikar, Suhas
A1 Soundararajan, Rama
A1 Sreekumar, Arun
A1 Mani, Sendurai A
K1 EMT
K1 FOXC2
K1 GLS2
K1 breast cancer
K1 glutamine metabolism
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.
SN 2072-6694
YR 2019
FD 2019-10-22
LK https://hdl.handle.net/10668/25034
UL https://hdl.handle.net/10668/25034
LA en
DS RISalud
RD Apr 7, 2025