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The mTORC1/S6K1 Pathway Regulates Glutamine Metabolism through the eIF4B-Dependent Control of c-Myc Translation

2014; Elsevier BV; Volume: 24; Issue: 19 Linguagem: Inglês

10.1016/j.cub.2014.08.007

1879-0445

Alfredo Csibi, Gina Lee, Sang-Oh Yoon, Haoxuan Tong, Didem Ilter, Ilaria Elia, Sarah‐Maria Fendt, Thomas M. Roberts, John Blenis,

Metabolism, Diabetes, and Cancer

Growth-promoting signaling molecules, including the mammalian target of rapamycin complex 1 (mTORC1), drive the metabolic reprogramming of cancer cells required to support their biosynthetic needs for rapid growth and proliferation [1Howell J.J. Ricoult S.J. Ben-Sahra I. Manning B.D. A growing role for mTOR in promoting anabolic metabolism.Biochem. Soc. Trans. 2013; 41: 906-912Crossref PubMed Scopus (127) Google Scholar]. Glutamine is catabolyzed to α-ketoglutarate (αKG), a tricarboxylic acid (TCA) cycle intermediate, through two deamination reactions, the first requiring glutaminase (GLS) to generate glutamate and the second occurring via glutamate dehydrogenase (GDH) or transaminases [2DeBerardinis R.J. Lum J.J. Hatzivassiliou G. Thompson C.B. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation.Cell Metab. 2008; 7: 11-20Abstract Full Text Full Text PDF PubMed Scopus (2891) Google Scholar]. Activation of the mTORC1 pathway has been shown previously to promote the anaplerotic entry of glutamine to the TCA cycle via GDH. Moreover, mTORC1 activation also stimulates the uptake of glutamine, but the mechanism is unknown [3Csibi A. Fendt S.M. Li C. Poulogiannis G. Choo A.Y. Chapski D.J. Jeong S.M. Dempsey J.M. Parkhitko A. Morrison T. et al.The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4.Cell. 2013; 153: 840-854Abstract Full Text Full Text PDF PubMed Scopus (428) Google Scholar]. It is generally thought that rates of glutamine utilization are limited by mitochondrial uptake via GLS, suggesting that, in addition to GDH, mTORC1 could regulate GLS. Here we demonstrate that mTORC1 positively regulates GLS and glutamine flux through this enzyme. We show that mTORC1 controls GLS levels through the S6K1-dependent regulation of c-Myc (Myc). Molecularly, S6K1 enhances Myc translation efficiency by modulating the phosphorylation of eukaryotic initiation factor eIF4B, which is critical to unwind its structured 5′ untranslated region (5′UTR). Finally, our data show that the pharmacological inhibition of GLS is a promising target in pancreatic cancers expressing low levels of PTEN.