Implication of RICTOR in the mTOR inhibitor-mediated induction of insulin-like growth factor-I receptor (IGF-IR) and human epidermal growth factor receptor-2 (Her2) expression in gastrointestinal cancer cells

Biochim Biophys Acta. 2010 Apr;1803(4):435-42. doi: 10.1016/j.bbamcr.2010.01.009. Epub 2010 Jan 28.


Inhibition of mTORC1 with the mTOR inhibitor rapamycin may lead to an induction of Akt phosphorylation in cancer cells via mTORC2 activation. Using gastric and pancreatic cancer cells, we further investigated this paradoxical signaling response and found that rapamycin additionally up-regulates both IGF-IR and Her2 expression. Using RNAi for down-regulating RICTOR, this induction of receptor kinase expression was identified to be mediated via an mTORC2-induced Akt activation. Moreover, mTORC2 inhibition reduced the phosphorylation of GSK-3 and NF-kappaB, and significantly impaired cancer cell motility. In conclusion, inhibition of mTORC2 may abrogate unfavorable signaling effects of mTOR inhibitors, hence providing a novel rationale for therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Western
  • Carrier Proteins / metabolism*
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Glycogen Synthase Kinase 3 / metabolism
  • Humans
  • NF-kappa B / metabolism
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology
  • Phosphorylation
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / pharmacology
  • Rapamycin-Insensitive Companion of mTOR Protein
  • Receptor, ErbB-2 / metabolism*
  • Receptor, IGF Type 1 / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Sirolimus / pharmacology
  • Stomach Neoplasms / metabolism*
  • Stomach Neoplasms / pathology
  • Transcription Factors / physiology*


  • CRTC2 protein, human
  • Carrier Proteins
  • NF-kappa B
  • RICTOR protein, human
  • RNA, Messenger
  • RNA, Small Interfering
  • Rapamycin-Insensitive Companion of mTOR Protein
  • Transcription Factors
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Receptor, IGF Type 1
  • Glycogen Synthase Kinase 3
  • Sirolimus