Abstract
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+ cells, indicating its role in CSC regeneration. mTORC2 inhibitor directed the reduction of hedgehog pathway proteins and also reduced CSCs. Thus, our observations support a role for elevated mTORC2 activity in regulating angiogenesis, metastasis, cellular proliferation and CSC regeneration via hedgehog pathway activity. Taken together, it provides a rationale for including the mTOR2 inhibitor as part of the therapeutic regimen for CSCs.
Highlights
Glioblastoma multiforme (GBM) represents the most common form of malignant brain tumors in adults with extremely low survival rate.[1]
Differential mTORC2 activity leads to disparity in expression of Hh pathway proteins in GBM cells
We found an enhanced level of Gli[2] protein, which further leads to activation of other Hh pathway molecules such as Gli[1] and Ptch[1], as well as downstream target molecules such as Cyclin D1, Cyclin D2, VEGF, Snail and Slug both at mRNA and protein levels
Summary
Glioblastoma multiforme (GBM) represents the most common form of malignant brain tumors in adults with extremely low survival rate.[1]. We observed higher expression of Gli reporter genes in U87MG compared with LN229, suggesting a connection of the Hh pathway with the differential basal level of mTORC2 activity.
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