In addition to using glucose to support their energy requirements, proliferating cells can also use glutamine. Two sequential deamination reactions catalyzed by glutaminase and glutamate dehydrogenase (GDH), respectively, convert glutamine to α-ketoglutarate, a key component of the TCA cycle. Noting that mammalian target of rapamycin complex 1 (mTORC1) mediates increased nutrient uptake and metabolism, Csibi et al. investigated whether it was involved in glutamine metabolism. In mouse embryonic fibroblasts deficient in the mTORC1 inhibitor Tsc2 (Tsc2–/– MEFs), glutamine uptake was increased compared with that in wild-type MEFs. Glutamine uptake by DLD1 colon carcinoma cells was inhibited by rapamycin, an inhibitor of mTORC1, and analysis of glutamine metabolism showed that GDH activity was reduced in rapamycin-treated cells. The sirtuin family member SIRT4 inhibits GDH through ADP-ribosylation of the enzyme. The authors found that SIRT4 abundance was increased in rapamycin-treated Tsc2–/– MEFs compared with that in untreated Tsc2–/– MEFs, suggesting that mTORC1 activity repressed SIRT4 production. The transcription factor CREB2 is required for expression of the gene encoding SIRT4, and Western blotting analysis showed that mTORC1 activity resulted in the βTrCP-mediated ubiquitination and degradation of CREB2. Expression of SIRT4 in Tsc2–/– MEFs repressed the mTORC1-dependent increase in glutamine consumption, and expression of SIRT4 in DLD1 cells decreased both glutamine consumption and cellular proliferation. Expression of SIRT4 in the context of a mouse xenograft tumor model resulted in decreased proliferation and tumor volume, and studies of various human cancers showed that SIRT4 abundance was decreased in malignant cells compared with normal cells. Combined treatment of PTEN–/– MEFs (which have enhanced mTORC1 activity) or a prostate cancer cell line with both mechlorethamine (an alkylating agent that inhibits glycolysis) and EGCG (a GDH inhibitor) resulted in synergistic induction of cell death. Together, these data indicate that mTORC1, through the repression of SIRT4, promotes glutamine metabolism and cell proliferation and suggest that blocking nutrient metabolism may be an effective therapy against cancers with enhanced mTORC1 signaling.
A. Csibi, S.-M. Fendt, C. Li, G. Poulogiannis, A. Y. Choo, D. J. Chapski, S. M. Jeong, J. M. Dempsey, A. Parkhitko, T. Morrison, E. P. Henske, M. C. Haigis, L. C. Cantley, G. Stephanopoulos, J. Yu, J. Blenis, The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4. Cell 153, 840–854 (2013). [PubMed]