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

Sven A Lang; Christina Hackl; Christian Moser; Stefan Fichtner-Feigl; Gudrun E Koehl; Hans J Schlitt; Edward K Geissler; Oliver Stoeltzing

doi:10.1016/j.bbamcr.2010.01.009

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.

Authors

Sven A Lang¹, Christina Hackl, Christian Moser, Stefan Fichtner-Feigl, Gudrun E Koehl, Hans J Schlitt, Edward K Geissler, Oliver Stoeltzing

Affiliation

¹ Department of Surgery, University Medical Center Regensburg, Regensburg, Germany. sven.lang@klinik.uni-regensburg.de

PMID: 20116405
DOI: 10.1016/j.bbamcr.2010.01.009

Abstract

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*

Substances

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