Cross regulation between mTOR signaling and O-GlcNAcylation

Abstract

The hexosamine biosynthetic pathway (HBP) integrates glucose, amino acids, fatty acids and nucleotides metabolisms for uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) synthesis. UDP-GlcNAc is the nucleotide sugar donor for O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) processes. O-GlcNAc transferase (OGT) is the enzyme which transfers the N-acetylglucosamine (O-GlcNAc) residue onto target proteins. Several studies previously showed that glucose metabolism dysregulations associated with obesity, diabetes or cancer correlated with an increase of OGT expression and global O-GlcNAcylation levels. Moreover, these diseases present an increased activation of the nutrient sensing mammalian target of rapamycin (mTOR) pathway. Other works demonstrate that mTOR regulates protein O-GlcNAcylation in cancer cells through stabilization of OGT. In this context, we studied the cross-talk between these two metabolic sensors in vivo in obese mice predisposed to diabetes and in vitro in normal and colon cancer cells. We report that levels of OGT and O-GlcNAcylation are increased in obese mice colon tissues and colon cancer cells and are associated with a higher activation of mTOR signaling. In parallel, treatments with mTOR regulators modulate OGT and O-GlcNAcylation levels in both normal and colon cancer cells. However, deregulation of O-GlcNAcylation affects mTOR signaling activation only in cancer cells. Thus, a crosstalk exists between O-GlcNAcylation and mTOR signaling in contexts of metabolism dysregulation associated to obesity or cancer.

Cross-Dysregulation of O-GlcNAcylation and PI3K/AKT/mTOR Axis in Human Chronic Diseases

“…Since it was observed that pharmacological inhibition of mTOR enhances proteasomal and autophagic degradation of OGT in HepG2 cells ( 34 ). We have also demonstrated that inhibition of mTOR affects OGT protein level and overall O -GlcNAcylation levels in HCT116 colon cancer cell line ( 35 ). In breast cancer cell lines the positive regulation of OGT expression through mTOR is dependent on c-Myc-induced heat shock protein 90A (HSP90A) transcription ( 36 ).…”

“…Finally, it was shown that O -GlcNAcylation regulates the mitogenic mTOR signaling pathway through targeting the mTOR inhibitor AMPK ( 35 , 52 , 53 ). Increased O -GlcNAcylation in colon cancer cells, either by OGT overexpression or OGA inhibition, reduces phosphorylation of AMPK at Thr172, activates mTOR and induces cell growth in vitro in LoVo cell line and in vivo in LoVo cell-derived tumors of BALB/c-nu/nu mice ( 52 ).…”

Real Talk: The Inter-play Between the mTOR, AMPK, and Hexosamine Biosynthetic Pathways in Cell Signaling

“…Obesity is another area of research that has revealed a dynamic between mTOR and O-GlcNAc. When analyzing normal mice and Ob/Ob type mice, there were increased levels of OGT expression and mTOR phosphorylation ( 56 ). A corresponding in vitro experiment using colon cancer cells also demonstrated higher OGT expression and phosphorylated mTOR, as well as higher levels of O-GlcNAcylation.…”

“…A corresponding in vitro experiment using colon cancer cells also demonstrated higher OGT expression and phosphorylated mTOR, as well as higher levels of O-GlcNAcylation. Treatment of these cell lines with an mTOR activator (MHY1485) showed a slight increase in phosphorylated mTOR, OGT, and O-GlcNAcylation and a significant amplification in phosphorylated p70S6K ( 56 ). On the other hand, treatment with an mTOR inhibitor, rapamycin, caused distinct decreases in phosphorylated mTOR, OGT, O-GlcNAcylation and complete inhibition of p70S6K phosphorylation ( 56 ).…”

Hyperglycemia enhances cancer immune evasion by inducing alternative macrophage polarization through increased O-GlcNAcylation

“…Several proteins which regulate macrophage function, i.e. Akt/mTOR, HIFa, as well as the NFκB and NFAT families [35,[45][46][47], were shown to be O-…”