Inhibition of mTOR complexes protects cancer cells from glutamine starvation induced cell death by restoring Akt stability

• Published in: Biochimica et biophysica acta. Molecular basis of disease Vol. 1864; no. 6; pp. 2040 - 2052
• Main Authors: Khan, Md. Wasim, Layden, Brian T., Chakrabarti, Partha
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.06.2018
• Subjects: Akt; Animals; Apoptosis - drug effects; Autophagy; Autophagy - drug effects; Cancer metabolism; Cell Line, Tumor; Cell survival; Cell Survival - drug effects; Glutamine; Glutamine - deficiency; Humans; Mice; mTOR; Neoplasms - drug therapy; Neoplasms - pathology; NIH 3T3 Cells; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Protein Stability; Proteolysis - drug effects; Proto-Oncogene Proteins c-akt - metabolism; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - metabolism; Ubiquitination - drug effects; mTOR; Cell survival; Akt; Cancer metabolism; Autophagy; Glutamine
• ISSN: 0925-4439; 1879-260X
• DOI: 10.1016/j.bbadis.2018.03.013

Glutamine, a well-established oncometabolite, anaplerotically fuels mitochondrial energy metabolism and modulates activity of mammalian/mechanistic target of rapamycin complexes (mTOR). Currently, mTOR inhibitors are in clinical use for certain types of cancer but with limited success. Since glutamine is essential for growth of many cancers, we reasoned that glutamine deprivation under conditions of mTOR inhibition should be more detrimental to cancer cell survival. However, our results show that when cells are deprived of glutamine concomitant with mTOR inhibition, hepatocarcinoma cells elicit an adaptive response which aids in their survival due to enhanced autophagic flux. Moreover, inhibition of mTOR promotes Akt ubiquitination and its proteasomal degradation however we show that Akt degradation is abrogated by increased autophagy following glutamine withdrawal. Under conditions of glutamine deficiency and mTOR inhibition, the enhanced stability of Akt protein may provide survival cues to cancer cells. Thus, our data uncovers a novel molecular link between glutamine metabolism, autophagy and stability of Akt with cancer cell survival. •Glutamine deficiency enhances autophagy in mTOR inhibited cancer cells.•Akt is rescued by enhanced autophagy when mTOR is inhibited under glutamine stress.•Rescued Akt provides survival cues that protects cancer cells from cell death.