High Glucose modulates the cancer cell fate by regulation of mTOR-HDAC-microRNA axis

Abstract

Glioblastoma multiforme (GBM) is the most dangerous cancers of the brain. Despite availability of various treatment modalities, GBM chemotherapy remains obscure. Cancer metabolism is considered as one of the important factors for the tumor aggressiveness. Glucose is an important energy source for the cellular metabolism and was found to affect the GBM cancer aggressiveness, and chemo-resistance. Studies have found that GBM cancer is driven by epigenetic proteins. HDACs are important epigenetic proteins that regulate the gene expression by chromatin epigenetics changes, and there by involved in gene transcription in cancer cells. In this study, we have evaluated the role of glucose on GBM cancer cells and identified the cell viability effects. Further, the cell-cycle studies have indicated the apoptotic effects of high dose of glucose. Further the histone deacetylase (HDAC) gene expression was examined during increased glucose availability. We have observed a drastic enhancement in HDAC gene expression. Further, the cancer cell metabolism was analysed by studying the gene expression pertaining to mammalian target of rapamycin (mTOR) pathway. Glucose has induced changes in gene expression of class I HDACs and mTOR pathway genes. Furthermore, the study has also identified the microRNA modulatory effect of glucose. The molecular modelling studies have indicated the interaction of glucose with mTOR, Rictor and caspase-3 proteins suggesting the functional regulatory role of glucose on the expression of genes. The caspase-3 (i. e. the effector caspase) studies confirmed the effect of glucose on caspase-3 activity and the effect was enhanced by the treatment with mTOR complex inhibitors. Proteomic study has identifed the involvement of MAPK, Rho kinase, S6 kinase pathways, Bromodomain, histone acetyl transferases during combined treatment of mTOR complex inhibitor and high glucose combination treatment. Thus, the present study has elucidated the role of glucose on GBM cancer proliferation, and molecular modulatory effect mediated by glucose by varying the chromatin epigenetics, and microRNA modulation.