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 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.
Highlights
Breast cancer is a heterogeneous disease and despite successes in targeted therapy of some subtypes, treatment still remains a clinical challenge.[1]
We show that glutamate pyruvate transaminase 2 (GPT2), which serves as a pivot between glycolysis and glutaminolysis, is highly upregulated in aggressive breast cancers, the triple-negative breast cancer subtype
We found the enzyme GPT2 to be significantly higher expressed in triple-negative breast cancer (TNBC) tumors as compared to the other breast cancer subtypes (Figure 1A) within a proteomic data set of a prospective multicenter cohort of 800 breast cancer patients, the PiA cohort.[14]
Summary
Breast cancer is a heterogeneous disease and despite successes in targeted therapy of some subtypes, treatment still remains a clinical challenge.[1]. Known as “the Warburg effect,” is the most commonly reported metabolic characteristic in tumors.[4] In addition to the Warburg effect, glutamine addiction is commonly observed in several cancer types as glutamine is the second most important carbon source after glucose. This fuels the tricarboxylic acid (TCA) cycle to provide both energy and biosynthetic precursors.[5] Glutamine is broken down in the cells and distributed into different nonessential amino acids via transaminase reactions to produce α-ketoglutarate (α-KG), a key metabolite of the TCA cycle. Loss of GPT2 inhibits tumor growth in vivo, corroborating GPT2 as a critical enzyme in oncogenesis in TNBC by playing a crucial role in maintaining a balance between opposing nutrient sensing mechanisms
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