Abrogating GPT2 in triple-negative breast cancer inhibits tumor growth and promotes autophagy
| Autor: | Karin Müller-Decker, Aristotelis Chatziioannou, Stefan Wiemann, Christoph Thomssen, Nooraldeen Tarade, Heike Wilhelm, Martina Vetter, Rüdiger Hell, Nadine Royla, Silvia Vega-Rubin-de-Celis, Stefan Kempa, Ilona Binenbaum, Michael Buettner, Simone Borgoni, Gernot Poschet, Devina Mitra, Stephan Bernhardt, Eva Johanna Kantelhardt |
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| Rok vydání: | 2020 |
| Předmět: |
Cancer Research
Medizin Triple Negative Breast Neoplasms mTORC1 Mice SCID medicine.disease_cause 03 medical and health sciences Gene Knockout Techniques 0302 clinical medicine Mice Inbred NOD Cell Line Tumor medicine Autophagy Animals Humans Glycolysis Triple-negative breast cancer Transaminases Mice Knockout Glutaminolysis Chemistry Cancer medicine.disease Survival Analysis Xenograft Model Antitumor Assays Tumor Burden Gene Expression Regulation Neoplastic Oncology 030220 oncology & carcinogenesis Cancer cell Cancer research MCF-7 Cells Female RNA Interference CRISPR-Cas Systems Carcinogenesis |
| Zdroj: | International journal of cancerREFERENCES. 148(8) |
| ISSN: | 1097-0215 |
| Popis: | 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 subtype. Abrogation of this enzyme results in decreased tricarboxylic acid 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 activity as well as the induction of autophagy. Furthermore, in vivo xenograft 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. |
| Databáze: | OpenAIRE |
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