Publication: Glutamine metabolism regulates FLIP expression and sensitivity to TRAIL in triple-negative breast cancer cells.
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Date
2018-02-12
Authors
Mauro-Lizcano, Marta
López-Rivas, Abelardo
Advisors
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Abstract
Glutamine plays an important role in the metabolism of tumor cells through its contribution to redox homeostasis, bioenergetics, synthesis of macromolecules, and signaling. Triple-negative breast cancers (TNBC) are highly metastatic and associated with poor prognosis. TNBC cells show a marked dependence on extracellular glutamine for growth. Herein we demonstrate that TNBC cells are markedly sensitized to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis upon glutamine deprivation. Upregulation of pro-apoptotic TRAIL receptor 2 (TRAIL-R2/DR5) and downregulation of FLICE-inhibitory protein (FLIP) are observed in glutamine-deprived TNBC cells. Activation of the amino-acid-sensing kinase general control nonderepressible 2 (GCN2) upon glutamine deprivation is responsible for TRAIL-R2 upregulation through a signaling pathway involving ATF4 and CHOP transcription factors. In contrast, FLIP downregulation in glutamine-deprived TNBC occurs by a GCN2-independent mechanism. Importantly, silencing FLIP expression by RNA interference results in a marked sensitization of TNBC cells to TRAIL-induced apoptosis. In addition, pharmacological or genetic inhibition of transaminases increases TRAIL-R2 expression and downregulates FLIP levels, sensitizing TNBC cells to TRAIL. Interestingly, treatment with L-asparaginase markedly sensitizes TNBC cells to TRAIL through its glutaminase activity. Overall, our findings suggest that targeting the glutamine addiction phenotype of TNBC can be regarded as a potential antitumoral target in combination with agonists of proapoptotic TRAIL receptors.
Description
MeSH Terms
CASP8 and FADD-Like Apoptosis Regulating Protein
Down-Regulation
Female
Gene Expression Regulation, Neoplastic
Glutamine
Humans
MCF-7 Cells
Neoplasm Proteins
TNF-Related Apoptosis-Inducing Ligand
Triple Negative Breast Neoplasms
Down-Regulation
Female
Gene Expression Regulation, Neoplastic
Glutamine
Humans
MCF-7 Cells
Neoplasm Proteins
TNF-Related Apoptosis-Inducing Ligand
Triple Negative Breast Neoplasms