The mTORC1 Pathway Stimulates Glutamine Metabolism and Cell Proliferation by Repressing SIRT4

Abstract

Summary Proliferating mammalian cells use glutamine as a source of nitrogen and as a key anaplerotic source to provide metabolites to the tricarboxylic acid cycle (TCA) for biosynthesis. Recently, mTORC1 activation has been correlated with increased nutrient uptake and metabolism, but no molecular connection to glutaminolysis has been reported. Here, we show that mTORC1 promotes glutamine anaplerosis by activating glutamate dehydrogenase (GDH). This regulation requires transcriptional repression of SIRT4, the mitochondrial-localized sirtuin that inhibits GDH. Mechanistically, mTORC1 represses SIRT4 by promoting the proteasome-mediated destabilization of cAMP response element binding-2 (CREB2). Thus, a relationship between mTORC1, SIRT4 and cancer is suggested by our findings. Indeed, SIRT4 expression is reduced in human cancer, and its overexpression reduces cell proliferation, transformation and tumor development. Finally, our data indicate that targeting nutrient metabolism in energy-addicted cancers with high mTORC1 signaling may be an effective therapeutic approach.

Mitochondrial Sirtuins and Their Relationships with Metabolic Disease and Cancer

“…Inhibition of mTORC1 activity by rapamycin results in increased SIRT4 expression and reduced GDH activity in Tsc2 KO cells (30). Consistently, SIRT4 overexpression inhibits transformation and proliferation of Tsc2 KO MEFs in vitro, and delays tumor development in xenograft models (30).…”

“…Recent studies confirmed that SIRT4 indeed acts as a tumor suppressor, by repressing glutamine metabolism and promoting genomic stability (30,69,71). Glutamine is a key amino acid required for diverse intracellular processes such as macromolecular synthesis, redox homeostasis, oxidative metabolism, and many others (95).…”

“…Csibi et al showed that a mechanistic target of rapamycin complex 1 (mTORC1) negatively regulates SIRT4 expression by promoting proteasome-mediated degradation of the SIRT4 transcriptional regulator CREB2 (30). Tuberous sclerosis 2 (TSC2) is a negative regulator of mTORC1; thus, Tsc2 KO MEFs show increased mTORC1 activation.…”

Glutamine at focus: versatile roles in cancer

“…Likewise, another report has demonstrated that mTORC1 activation regulates positively, GDH; this launches a robustly anabolic response through glutamine catabolism. Mechanistically, it has been shown to involve Sirt4/CREB2 repression/degradation (see BSirt4 and Hace1^) [74]. Another study has demonstrated a key insight into the role of mTORC1 and Myc as central regulators of glutaminolysis.…”

“…Remarkably, documenting a relationship between mTORC1 and Sirt4 has provided insights into tumor biology. Csibi et al have showed that mTOR1 regulates GDH heightening glutamine catabolism (anaplerosis) through destabilization of the cAMP response element binding-2 (CREB2), which decreases Sirt4 expression [74].…”