mahanine and Glioblastoma

mTORC2 is aberrantly activated in cancer and therefore is considered to be an important therapeutic target. The hedgehog pathway, which is also often hyperactivated, regulates transcription of several genes associated with angiogenesis, metastasis, cellular proliferation and cancer stem cell (CSC) regeneration. However, the contribution of mTORC2 toward hedgehog pathway activity has not been explored yet. Here we have addressed the molecular cross talk between mTORC2 and hedgehog pathway activities in the context of glioblastoma multiforme, a malignant brain tumor using as a model system. We observed that higher mTORC2 activity enhanced the expression of a few hedgehog pathway molecules (Gli1, Gli2 and Ptch1) and amplified its target genes (Cyclin D1, Cyclin D2, Cyclin E, Snail, Slug and VEGF) both in mRNA and protein levels as corroborated by increased metastasis, angiogenesis, cellular proliferation and stem cell regeneration. Inhibition of mTORC2 formation decreased hedgehog pathway activity and attenuated all these above-mentioned events, suggesting their cross talk with each other. Further investigations revealed that mTORC2 inhibited ubiquitination of Gli2 by inactivating GSK3β, and thus it promotes stability to Gli2 and its nuclear translocation. Moreover, enhanced mTORC2 activity led to the increased clonogenic properties and CD133

Topics: Carbazoles; Cell Line, Tumor; Cell Movement; Cell Nucleus; Cell Proliferation; Cell Survival; Cyclin E; Glioblastoma; Glycogen Synthase Kinase 3 beta; Hedgehog Proteins; Humans; Mechanistic Target of Rapamycin Complex 2; Neoplastic Stem Cells; Nuclear Proteins; Rapamycin-Insensitive Companion of mTOR Protein; Signal Transduction; Snail Family Transcription Factors; Vascular Endothelial Growth Factor A; Zinc Finger Protein GLI1; Zinc Finger Protein Gli2