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Glutamine metabolism regulates FLIP expression and sensitivity to TRAIL in triple-negative breast cancer cells.

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.

SUBMITTER: Mauro-Lizcano M

PROVIDER: S-EPMC5833863 | biostudies-other | 2018 Feb

REPOSITORIES: biostudies-other

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Glutamine metabolism regulates FLIP expression and sensitivity to TRAIL in triple-negative breast cancer cells.

Mauro-Lizcano Marta M López-Rivas Abelardo A

Cell death & disease 20180212 2

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 glut ...[more]

PMID: 29434187

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Project description:Blockade of programmed cell death 1 ligand (PD-L1) has been used to treat triple-negative breast cancer (TNBC), and various strategies are under investigation to improve the treatment response rate. Inhibition of glutamine metabolism can reduce the massive consumption of glutamine by tumor cells and meet the demand for glutamine by lymphocytes in tumors, thereby improving the anti-tumor effect on the PD-L1 blockade therapy. Here, molybdenum disulfide (MoS2) was employed to simultaneously deliver anti-PDL1 antibody (aPDL1) and V9302 to boost the anti-tumor immune response in TNBC cells. The characterization results show that MoS2 has a dispersed lamellar structure with a size of about 181 nm and a size of 232 nm after poly (L-lysine) (PLL) modification, with high stability and biocompatibility. The loading capacity of aPDL1 and V9302 are 3.84% and 24.76%, respectively. V9302 loaded MoS2 (MoS2-V9302) can effectively kill 4T1 cells and significantly reduce glutamine uptake of tumor cells. It slightly increases CD8+ cells in the tumor and promotes CD8+ cells from the tumor edge into the tumor core. In vivo studies demonstrate that the combination of aPDL1 and V9302 (MoS2-aPDL1-V9302) can strongly inhibit the growth of TNBC 4T1 tumors. Interestingly, after the treatment of MoS2-aPDL1-V9302, glutamine levels in tumor interstitial fluid increased. Subsequently, subtypes of cytotoxic T cells (CD8+) in the tumors were analyzed according to two markers of T cell activation, CD69, and CD25, and the results reveal a marked increase in the proportion of activated T cells. The levels of cytokines in the corresponding tumor interstitial fluid are also significantly increased. Additionally, during the treatment, the body weights of the mice remain stable, the main indicators of liver and kidney function in the blood do not increase significantly, and there are no obvious lesions in the main organs, indicating low systemic toxicity. In conclusion, our study provides new insights into glutamine metabolism in the tumor microenvironment affects immune checkpoint blockade therapy in TNBC, and highlights the potential clinical implications of combining glutamine metabolism inhibition with immune checkpoint blockade in the treatment of TNBC.

Dataset Information

Glutamine metabolism regulates FLIP expression and sensitivity to TRAIL in triple-negative breast cancer cells.

Publications

Glutamine metabolism regulates FLIP expression and sensitivity to TRAIL in triple-negative breast cancer cells.

Similar Datasets

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