mTOR as a positive regulator of tumor cell responses to hypoxia

Curr Top Microbiol Immunol. 2004;279:299-319. doi: 10.1007/978-3-642-18930-2_18.

Abstract

Rapamycin is a clinically approved immunosuppressive agent that has recently shown promising antitumor activities in human patients. In contrast to many conventional chemotherapeutic agents, rapamycin displays a remarkably high level of selectivity for certain types of tumors. The pharmacological activities of rapamycin are attributable to the functional inhibition of a single target protein, termed the mammalian target of rapamycin (mTOR). Because mTOR is widely expressed in both normal and transformed cells, variations in mTOR expression levels are likely not a primary determinant of tumor sensitivity to rapamycin. However, recent studies highlighted an intriguing link between cancer cell sensitivity to rapamycin and deregulated signaling through the phosphoinositide (PI) 3-kinase pathway. These findings have prompted a search for cancer-related responses that are jointly regulated by the PI 3-kinase signaling cascade and mTOR. The oxygen-regulated transcription factor, hypoxia-induced factor (HIF)-1, has emerged as a candidate target for both of these two highly interactive signaling proteins. Here we review evidence that mTOR functions as a positive regulator of HIF-1-dependent responses to hypoxic stress in human cancer cells.

Publication types

  • Review

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / pharmacology*
  • Cell Hypoxia / physiology
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology*
  • Humans
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Neoplasms / enzymology*
  • Neoplasms / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / physiology*
  • Protein Kinases / metabolism
  • Protein Kinases / physiology*
  • Sirolimus / pharmacology*
  • TOR Serine-Threonine Kinases
  • Transcription Factors*
  • Transcription, Genetic / physiology
  • Tumor Cells, Cultured

Substances

  • Antibiotics, Antineoplastic
  • DNA-Binding Proteins
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Nuclear Proteins
  • Transcription Factors
  • Protein Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Sirolimus