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

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.

Mitochondrial pyruvate supports lymphoma proliferation by fueling a glutamate pyruvate transaminase 2–dependent glutaminolysis pathway

“…1C). Although GPT2-mediated glutamate production has been shown to support cell proliferation in non-small cell lung cancer and breast cancer cell lines (19,20), it is the reverse reaction that produces -KG, which is important for cell proliferation in the majority of colorectal (21)(22)(23) and other cancers (24)(25)(26)(27)(28).…”

Exosomal GPT2 derived from triple‐negative breast cancer cells promotes metastasis by activating BTRC

“…It has been reported that GPT2 promoted tumorigenesis and stemness in breast cancer in previous research 15,16 . We speculated that GPT2 may play other roles in cancer progression.…”

“…Glutamate pyruvate transaminase 2 (GPT2) encodes a mitochondrial alanine transaminase, a pyridoxal enzyme that catalyzes the reversible transamination between alanine and 2‐oxoglutarate to generate pyruvate and glutamate. It is known that GPT2 is widely expressed in certain cancers including breast cancer and promotes tumorigenesis and stemness of breast cancer cells 15,16 . However, whether exosomal GPT2 participates in breast cancer progression remains unknown.…”

A Multi-Omics Approach to Evaluate the Toxicity Mechanisms Associated with Silver Nanoparticles Exposure

“…The inhibition of GLUD1 has also been related to increased ROS levels and, thus, oxidative stress, since GLUD1 inhibition leads to a decrease in fumarate levels, which finally leads to decreased glutathione peroxidases activity [ 36 ]. Additionally, the transcript encoding enzyme GPT2, which catalyzes the reversible transformation between α-ketoglutarate and glutamate, was also found to be downregulated (FC = 0.11); this is associated with the decrease in TCA cycle intermediates [ 37 ]. Thus, it can be concluded that AgNPs also impair some cellular defense mechanisms for facing the generated oxidative stress.…”