Opposing Roles for Calcineurin and ATF3 in Squamous Skin Cancer

Nature. 2010 May 20;465(7296):368-72. doi: 10.1038/nature08996.

Abstract

Calcineurin inhibitors such as cyclosporin A (CsA) are the mainstay of immunosuppressive treatment for organ transplant recipients. Squamous cell carcinoma (SCC) of the skin is a major complication of treatment with these drugs, with a 65 to 100-fold higher risk than in the normal population. By contrast, the incidence of basal cell carcinoma (BCC), the other major keratinocyte-derived tumour of the skin, of melanoma and of internal malignancies increases to a significantly lesser extent. Here we report that genetic and pharmacological suppression of calcineurin/nuclear factor of activated T cells (NFAT) function promotes tumour formation in mouse skin and in xenografts, in immune compromised mice, of H-ras(V12) (also known as Hras1)-expressing primary human keratinocytes or keratinocyte-derived SCC cells. Calcineurin/NFAT inhibition counteracts p53 (also known as TRP53)-dependent cancer cell senescence, thereby increasing tumorigenic potential. ATF3, a member of the 'enlarged' AP-1 family, is selectively induced by calcineurin/NFAT inhibition, both under experimental conditions and in clinically occurring tumours, and increased ATF3 expression accounts for suppression of p53-dependent senescence and enhanced tumorigenic potential. Thus, intact calcineurin/NFAT signalling is critically required for p53 and senescence-associated mechanisms that protect against skin squamous cancer development.

Publication types

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

MeSH terms

  • Activating Transcription Factor 3 / metabolism*
  • Animals
  • Calcineurin / deficiency
  • Calcineurin / genetics
  • Calcineurin / metabolism*
  • Calcineurin Inhibitors
  • Carcinoma, Squamous Cell / chemically induced
  • Carcinoma, Squamous Cell / metabolism*
  • Carcinoma, Squamous Cell / pathology*
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism
  • Cells, Cultured
  • Cellular Senescence
  • Cyclosporine / pharmacology
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • Humans
  • Keratinocytes / metabolism
  • Keratinocytes / pathology
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • NFATC Transcription Factors / antagonists & inhibitors
  • NFATC Transcription Factors / deficiency
  • NFATC Transcription Factors / genetics
  • NFATC Transcription Factors / metabolism
  • Neoplasm Transplantation
  • Signal Transduction
  • Skin Neoplasms / chemically induced
  • Skin Neoplasms / metabolism*
  • Skin Neoplasms / pathology*
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • ATF3 protein, human
  • Activating Transcription Factor 3
  • Calcineurin Inhibitors
  • NFATC Transcription Factors
  • Tumor Suppressor Protein p53
  • Cyclosporine
  • Calcineurin