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mTORC2 regulates hedgehog pathway activity by promoting stability to Gli2 protein and its nuclear translocation

Samarpan Maiti1, Susmita Mondal1, Eswara M Satyavarapu1

  • 1Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur, Kolkata 700032, India.

Cell Death & Disease
|July 14, 2017
PubMed

Insights

Mammalian target of rapamycin complex 2 (mTORC2) signaling enhances the hedgehog pathway, promoting glioblastoma growth, metastasis, and cancer stem cell regeneration. Inhibiting mTORC2 reduces these effects, suggesting mTORC2 as a therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Aberrant activation of mammalian target of rapamycin complex 2 (mTORC2) is implicated in cancer, making it a key therapeutic target.
  • The hedgehog signaling pathway is frequently hyperactivated in cancer, regulating genes involved in angiogenesis, metastasis, proliferation, and cancer stem cell (CSC) regeneration.

Purpose of the Study:

  • To investigate the molecular crosstalk between mTORC2 and the hedgehog pathway in glioblastoma multiforme.
  • To determine the role of mTORC2 in regulating hedgehog pathway activity and its downstream effects on cancer progression and CSCs.

Main Methods:

  • Utilized glioblastoma multiforme as a model system to study the interaction between mTORC2 and the hedgehog pathway.
  • Assessed the expression of hedgehog pathway molecules (Gli1, Gli2, Ptch1) and target genes (Cyclin D1/D2/E, Snail, Slug, VEGF) at mRNA and protein levels.
  • Investigated the effect of mTORC2 inhibition on hedgehog pathway activity, cancer cell proliferation, metastasis, angiogenesis, and CSC regeneration, including Gli2 ubiquitination and GSK3β activity.

Main Results:

  • Elevated mTORC2 activity increased the expression of hedgehog pathway components and amplified its target genes, correlating with enhanced metastasis, angiogenesis, proliferation, and CSC regeneration.
  • Inhibition of mTORC2 decreased hedgehog pathway activity and attenuated these cancer-promoting events, indicating a significant crosstalk.
  • mTORC2 was found to inhibit Gli2 ubiquitination by inactivating GSK3β, thereby promoting Gli2 stability and nuclear translocation, leading to increased clonogenic properties and CD133+ cells.

Conclusions:

  • Elevated mTORC2 activity drives angiogenesis, metastasis, cellular proliferation, and CSC regeneration through the hedgehog pathway in glioblastoma.
  • mTORC2 inhibition effectively reduces hedgehog pathway proteins and CSCs, highlighting its therapeutic potential.
  • These findings provide a strong rationale for incorporating mTORC2 inhibitors into therapeutic regimens for targeting CSCs in glioblastoma.

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