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.