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Abrogating GPT2 in triple negative breast cancer inhibits tumor growth and promotes autophagy

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Item Type:Article
Title:Abrogating GPT2 in triple negative breast cancer inhibits tumor growth and promotes autophagy
Creators Name:Mitra, D., Vega-Rubin-de-Celis, S., Royla, N., Bernhardt, S., Wilhelm, H., Tarade, N., Poschet, G., Buettner, M., Binenbaum, I., Borgoni, S., Vetter, M., Kantelhardt, E.J., Thomssen, C., Chatziioannou, A., Hell, R., Kempa, S., Müller-Decker, K. and Wiemann, S.
Abstract:Uncontrolled proliferation and altered metabolic reprogramming are hallmarks of cancer. Active glycolysis and glutaminolysis are characteristic features of these hallmarks and required for tumorigenesis. A fine balance between cancer metabolism and autophagy is a prerequisite of homeostasis within cancer cells. Here we show that glutamate pyruvate transaminase 2 (GPT2), which serves as a pivot between glycolysis and glutaminolysis, is highly upregulated in aggressive breast cancers, particularly the triple negative breast cancer (TNBC) subtype. Abrogation of this enzyme results in decreased TCA cycle intermediates, which promotes the rewiring of glucose carbon atoms and alterations in nutrient levels. Concordantly, loss of GPT2 results in an impairment of mechanistic target of rapamycin complex 1 (mTORC1) activity as well as the induction of autophagy. Furthermore, in vivo xenografts studies have shown that autophagy induction correlates with decreased tumor growth and that markers of induced autophagy correlate with low GPT2 levels in patient samples. Taken together, these findings indicate that cancer cells have a close network between metabolic and nutrient sensing pathways necessary to sustain tumorigenesis, and that aminotransferase reactions play an important role in maintaining this balance.
Keywords:GPT2, mTORC1, Autophagy, Cancer Metabolism, Breast Cancer, Animals, Mice
Source:International Journal of Cancer
ISSN:0020-7136
Publisher:Wiley
Volume:148
Number:8
Page Range:1993-2009
Date:15 April 2021
Official Publication:https://doi.org/10.1002/ijc.33456
PubMed:View item in PubMed

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