The crosstalk of mTOR/S6K1 and Hedgehog pathways

Cancer Cell. 2012 Mar 20;21(3):374-87. doi: 10.1016/j.ccr.2011.12.028.

Abstract

Esophageal adenocarcinoma (EAC) is the most prevalent esophageal cancer type in the United States. The TNF-α/mTOR pathway is known to mediate the development of EAC. Additionally, aberrant activation of Gli1, downstream effector of the Hedgehog (HH) pathway, has been observed in EAC. In this study, we found that an activated mTOR/S6K1 pathway promotes Gli1 transcriptional activity and oncogenic function through S6K1-mediated Gli1 phosphorylation at Ser84, which releases Gli1 from its endogenous inhibitor, SuFu. Moreover, elimination of S6K1 activation by an mTOR pathway inhibitor enhances the killing effects of the HH pathway inhibitor. Together, our results established a crosstalk between the mTOR/S6K1 and HH pathways, which provides a mechanism for SMO-independent Gli1 activation and also a rationale for combination therapy for EAC.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / metabolism*
  • Animals
  • Cell Proliferation
  • Esophageal Neoplasms / genetics
  • Esophageal Neoplasms / metabolism*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Gene Expression Regulation, Neoplastic
  • Hedgehog Proteins / genetics
  • Hedgehog Proteins / metabolism*
  • Hedgehog Proteins / physiology
  • Humans
  • Models, Biological
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats
  • Repressor Proteins / physiology
  • Ribosomal Protein S6 Kinases, 70-kDa / genetics
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Ribosomal Protein S6 Kinases, 70-kDa / physiology*
  • Signal Transduction*
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism
  • TOR Serine-Threonine Kinases / physiology*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription Factors / physiology
  • Zinc Finger Protein GLI1

Substances

  • GLI1 protein, human
  • Hedgehog Proteins
  • Repressor Proteins
  • SUFU protein, human
  • Transcription Factors
  • Zinc Finger Protein GLI1
  • TOR Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases, 70-kDa
  • ribosomal protein S6 kinase, 70kD, polypeptide 1
  • Extracellular Signal-Regulated MAP Kinases