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  • Review Article
  • Published:

Prevention of non-melanoma skin cancer by targeting ultraviolet-B-light signalling

Nature Reviews Cancer volume 4, pages 23–35 (2004)Cite this article

Key Points

  • The incidence of non-melanoma skin cancers such as squamous-cell carcinoma (SCC) in many countries including the United States has been increasing recently with significant effects on public health. Primary prevention — for example, the use of sun screens — has proven inadequate in impacting the incidence of skin cancer, and this has stimulated the development of chemoprevention strategies.

  • Ultraviolet B (UVB) light acts as a tumour-initiating, -promoting and -progressing agent in the generation of SCC.

  • UVB light mediates skin-tumour promotion through activation of the transcription factor complex activator protein-1 (AP-1) and through the expression of the cyclooxygenase-2 (COX2) gene.

  • UVB light mediates AP-1 activation, which increases binding of the differentially phosphorylated cyclic-AMP-response-element-binding protein (CREB) to the CRE site and c-FOS AP-1 site within the promoter region of the c-FOS gene, so increasing transcription and expression of c-FOS.

  • UVB light mediates COX2 transcription through increased binding of differentially phosphorylated CREB to a CRE site in the promoter region of the COX2 gene.

  • UVB light induces increased phosphorylation of CREB at serine 133 through activation of p38 mitogen-activated protein kinase (MAPK), which results in increased transcription of the c-FOS and COX2 genes.

  • UVB light decreases phosphorylation of CREB at Ser129 through activation of the phosphatidylinositol 3-kinase (PI3K)–AKT pathway, which results in increased binding of CREB to the promoter regions of the c-FOS and COX2 genes and increased transcription.

  • Epigallocatechin gallate (EGCG) is an inhibitor of the UVB-light-induced p38 MAPK pathway and has shown chemopreventive activity in preventing UVB-light-induced skin-tumour development.

  • Nordihydroguaiaretic acid (NDGA) is an inhibitor of UVB-light-induced PI3K–AKT pathway and NDGA has been shown to have chemopreventive activity.

  • New chemopreventive agents that target UVB-light signalling pathways — leading to AP-1 activation and COX2 expression — are being translated into the clinic.

Abstract

The incidence of non-melanoma skin cancer is rising and primary prevention, including the use of sun screens, has proven inadequate in reducing this incidence. Chemoprevention strategies are therefore needed. Ultraviolet B light can initiate skin-tumour development through DNA damage and mutation in crucial target genes, and can also promote the clonal expansion of initiated cells to give rise to benign skin tumours. Targeting key molecules in the ultraviolet-light signal-transduction pathway is being explored for early chemoprevention of non-melanoma skin cancer.

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Figure 1: Stages of UVB-light-induced skin carcinogenesis.
Figure 2: UVB-light signalling pathway involving p38 and ERK leading to c-FOS transcription and AP-1 activation.
Figure 3: Prostaglandin synthesis pathway.
Figure 4: UVB-light signalling pathways involving p38 and PI3K leading to altered phosphorylation of CREB with increased transactivation of the c-FOS and COX2 promoters.

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Acknowledgements

This work is supported by grants from the National Cancer Institute.

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Authors and Affiliations

  1. Department of Cell Biology and Anatomy, Arizona Cancer Center, The University of Arizona, 1515 North Campbell Avenue, Tucson, 85724-5024, Arizona, USA

    G. Tim Bowden

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DATABASES

Cancer.gov

basal-cell skin cancer

melanoma

squamous-cell skin cancer

LocusLink

ATF1

ATF2

COX1

COX2

CREB

c-FOS

FOSB

FRA1

FRA2

Gsk-3β

c-JUN

JUNB

JUND

ODC

p38α

p38β2

p38γ

p42

p44

SAPK4

TP53

Glossary

LUCIFERASE REPORTER

Firefly luciferase is used as a non-mammalian foreign gene to report on the activity of a gene promoter which drives the expression of the foreign gene.

GLYCOGEN SYNTHASE KINASE-3β

(GSK-3β). A crucial downstream element of the phosphatidylinositol-3-kinase–AKT cell-survival pathway and its activity can be inhibited by AKT-mediated phosphorylation at serine 9 of GSK-3β.

LIGNAN

A class of dibenzylbutane derivatives that occurs in higher plants and in fluids in man and other animals. These compounds have a potential anticancer role.

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Bowden, G. Prevention of non-melanoma skin cancer by targeting ultraviolet-B-light signalling. Nat Rev Cancer 4, 23–35 (2004). https://doi.org/10.1038/nrc1253

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