Hypoxia signalling through mTOR and the unfolded protein response in cancer

Nat Rev Cancer. 2008 Nov;8(11):851-64. doi: 10.1038/nrc2501. Epub 2008 Oct 10.


Hypoxia occurs in the majority of tumours, promoting angiogenesis, metastasis and resistance to therapy. Responses to hypoxia are orchestrated in part through activation of the hypoxia-inducible factor family of transcription factors (HIFs). Recently, two additional O(2)-sensitive signalling pathways have also been implicated: signalling through the mammalian target of rapamycin (mTOR) kinase and signalling through activation of the unfolded protein response (UPR). Although they are activated independently, growing evidence suggests that HIF-, mTOR- and UPR-dependent responses to hypoxia act in an integrated way, influencing each other and common downstream pathways that affect gene expression, metabolism, cell survival, tumorigenesis and tumour growth.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Cell Hypoxia*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Protein Folding*
  • Protein Kinases / metabolism*
  • Signal Transduction*
  • TOR Serine-Threonine Kinases


  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Protein Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases