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

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 prev...

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Detalles Bibliográficos
Autores: Ramirez-Peña, Esmeralda, Arnold, James, Shivakumar, Vinita, Joseph, Robiya, Vidhya Vijay, Geraldine, den Hollander, Petra, Bhangre, Neeraja, Allegakoen, Paul, Prasad, Rishika, Conley, Zachary, Matés, José M, Márquez, Javier, Chang, Jeffrey T, Vasaikar, Suhas, Soundararajan, Rama, Sreekumar, Arun, Mani, Sendurai A
Tipo de recurso: artículo
Fecha de publicación:2019
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/17920
Acceso en línea:http://hdl.handle.net/20.500.12105/17920
Access Level:acceso abierto
Palabra clave:EMT
FOXC2
GLS2
Breast cancer
Glutamine metabolism
Descripción
Sumario: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.

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