Journal Article

Opposing roles for calcineurin and ATF3 in squamous skin cancer

Chang, Sungeun, Hofbauer, Günther F. L., Nguyen, Bach-Cuc, Lefort, Karine, Brooks, Yang, Dotto, G. Paolo, Wu, Xunwei, Dziunycz, Piotr

2010

Overview

Calcineurin versus ATF3 in cancer Squamous cell carcinoma (SCC) of the skin is a common complication of immunosuppressive treatment with calcineurin inhibitors in graft-recipient patients. Here it is shown that the intact calcineurin/NFAT signalling pathway is important for suppressing SCC development, with a key role for increased expression of the ATF3 transcription factor in tumorigenesis. Calcineurin inhibitors are the mainstay of immunosuppressive treatment for organ transplant recipients. However, treatment with these drugs commonly leads to squamous cell carcinoma (SCC) of the skin. It is shown here that an intact calcineurin/NFAT signalling pathway is important for suppressing SCC development. Inhibition of this pathway leads to increased expression of the ATF3 protein, which has a key role in tumorigenesis. 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 1 . 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 1 . 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/80/509 / 692/699/67/1813 / Activating transcription factor 3 / Activating Transcription Factor 3 - metabolism / Activator protein 1 / Animal tumors. Experimental tumors / Animals / Basal cell carcinoma / Binding sites / Biological and medical sciences / Calcineurin / Calcineurin - deficiency / Calcineurin - genetics / Calcineurin - metabolism / Calcineurin Inhibitors / Cancer / 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 / Cyclosporin A / Cyclosporine - pharmacology / Cysts / Diagnosis / Drugs / Experimental skin tumors / Gene Expression Regulation, Neoplastic / Gene Knockdown Techniques / Genes / Humanities and Social Sciences / Humans / Immunosuppressive agents / Inhibitors / Keratinocytes / Keratinocytes - metabolism / Keratinocytes - pathology / letter / Lymphocytes / Malignancy / Medical sciences / Melanoma / Mice / Mice, Inbred NOD / Mice, SCID / multidisciplinary / Mutation / Neoplasm Transplantation / NF-AT protein / NFATC Transcription Factors - antagonists & inhibitors / NFATC Transcription Factors - deficiency / NFATC Transcription Factors - genetics / NFATC Transcription Factors - metabolism / p53 Protein / Peptides / Physiological aspects / Proteins / Risk factors / Science / Science (multidisciplinary) / Senescence / Signal Transduction / Skin cancer / Skin Neoplasms - chemically induced / Skin Neoplasms - metabolism / Skin Neoplasms - pathology / Squamous cell carcinoma / Transcription factors / Tumor Suppressor Protein p53 - metabolism / Tumorigenesis / Tumors / Xenotransplantation