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Targeting UVB
Induced AP-1 Activation for Chemoprevention of Skin Cancer
Bowden, G. Tim1,
Chen, Weixing2, Gregus, Jacalyn1,
Tang, Qingbo1 and Dong, Zigang3
The University of Arizona, Tucson, AZ 857241
Scripps Research Institute, La Jolla, CA 920372
The Hormel Institute, Austin, MN 559123
Abstract-
Non-melanoma skin cancer caused by sunlight is a significant public
health problem in the US. The use of sunscreens is not totally effective
in preventing these cancers. Therefore, there is interest in developing
topical agents with different mechanisms of action to be used in combination
with sunscreens. Tumor promoting effects of UVB irradiation are, in
part, due to the activation of the transcription factor complex, activator
protein-1 (AP-1). This was demonstrated using transgenic mice expressing
a dominant negative mutant c-jun transgene in the epidermis. This transgene
inhibits UVB induced AP-1 activation in keratinocytes and UVB induced
skin tumors are inhibited in these transgenic mice. By understanding
the UVB signal transduction pathway in both cultured mouse and human
keratinocytes that leads to AP-1 activation we are developing agents
that block this signaling pathway at different points. We have found
in human keratinocytes that UVB induced AP-1 activation involves activation
of both p38 and ERK kinases that mediate transcriptional activation
of c-fos. In turn, c-Fos protein dimerizes with JunD to activate the
AP-1. We have investigated the mechanism of action of the chemoprevention
agent from green tea, (-)-epigallocatechin gallate (EGCG), and found
that EGCG inhibits UVB induced AP-1 activation by blocking p38 activation
which leads to c-fos transcription. We have also found that perillyl
alcohol that has been reported to inhibit ras farnesylation inhibits
UVB induced AP-1 activation in mouse skin and human keratinocytes. We
showed topical perillyl alcohol inhibits UVB induced mouse skin carcinogenesis.
Finally, we have recently shown that an AP-1 selective retinoid, SR11302,
inhibits UVB induced AP-1 activation in mouse skin and human keratinocytes.
This retinoid is being tested for its chemoprevention activity. Therefore,
we have demonstrated that agents that block UVB signal transduction
at different steps in signaling have chemoprevention activity in inhibiting
UVB induced mouse skin carcinogenesis.
Keywords: chemoprevention,
uvb-induced ap-1 activation, (-)-epigallocatechin gallate
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