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Abrogating GPT2 in triple‐negative breast cancer inhibits tumor growth and promotes autophagy
Author(s) -
Mitra Devina,
VegaRubindeCelis Silvia,
Royla Nadine,
Bernhardt Stephan,
Wilhelm Heike,
Tarade Nooraldeen,
Poschet Gernot,
Buettner Michael,
Binenbaum Ilona,
Borgoni Simone,
Vetter Martina,
Kantelhardt Eva Johanna,
Thomssen Christoph,
Chatziioannou Aristotelis,
Hell Rüdiger,
Kempa Stefan,
MüllerDecker Karin,
Wiemann Stefan
Publication year - 2021
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.33456
Subject(s) - glutaminolysis , autophagy , triple negative breast cancer , biology , citric acid cycle , cancer , anaerobic glycolysis , carcinogenesis , cancer research , glycolysis , cancer cell , breast cancer , chemistry , biochemistry , metabolism , apoptosis , genetics
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.