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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online April 18, 2005 as doi:10.1096/fj.04-3582fje. |
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,
,1
* Department of Dermatology;
University of Wisconsin Comprehensive Cancer Center;
Molecular and Environmental Toxicology Center, University of Wisconsin, Madison, Wisconsin, USA
1 Correspondence: Department of Dermatology, University of Wisconsin, Medical Science Center, 1300 University Ave., Madison, WI 53706, USA. E-mail: nahmad{at}wisc.edu
SPECIFIC AIMS
According to the World Cancer Report, skin cancer constitutes 
30% of all newly diagnosed cancers in the world and solar ultraviolet (UV) radiation, particularly its ultraviolet B (UVB) component (290–320 nm), is an established cause of 90% of skin cancers. Available options have proved inadequate for the management of skin cancer and other skin conditions caused by UVB radiation. Thus, novel mechanism-based approaches for management of skin cancer and other adverse effects of UVB radiation should be pursued. Chemoprevention, a newer dimension in the management of neoplasia (or other diseases), could offer a hope in this direction.
Trans-resveratrol (trans-3,4',5-trihydroxystilbene), a relatively new chemopreventive agent amply present in red wine and grapes, is believed to be responsible for the much-acclaimed phenomenon of the "French Paradox." Resveratrol has shown remarkable cancer chemopreventive effects in a variety of tumor bioassay models. Jang et al. demonstrated that resveratrol inhibited chemically induced skin tumorigenesis in a mouse model. Since a mouse model possesses only limited relevance to human skin cancers because solar UV radiation (rather than chemicals) is believed to be the major contributor to the development of skin cancers in humans, we designed this study to define the skin cancer chemopreventive effects of resveratrol in a photocarcinogenesis model of skin cancer that closely resembles human situations. We investigated our hypothesis that the skin cancer chemopreventive effects of resveratrol are mediated via modulations in the expression and function of survivin, a member of the inhibitor of apoptosis (IAP) gene family.
PRINCIPAL FINDINGS
1. Resveratrol imparts strong chemoprevention against the development of skin tumors in the SKH-1 hairless mouse model
We used SKH-1 hairless mice subjected to chronic UVB exposure (180 mJ/cm2, twice weekly) for 28 wk. This regimen resulted in a variety of skin tumors. To study skin cancer chemoprevention by resveratrol, we used two different protocols. In the first protocol, resveratrol (25 or 50 µmol/0.2 mL acetone/mouse) was topically applied to the mouse’s skin 30 min before each UVB exposure. The second protocol animals were exposed to UVB radiation followed (5 min later) by topical application of a similar amount of resveratrol. The later protocol (postapplication of resveratrol after UVB) was used to rule out the possibility that resveratrol might be acting solely as a sunscreen. Since resveratrol was applied when UVB radiations had already penetrated the skin, the effect observed does not appear to be a sunscreen effect.
As shown in Fig. 1
, our data clearly demonstrate that topical application of resveratrol on mouse skin (pre- and post-treatments) resulted in a highly significant inhibition of tumor incidence (% mice with tumors) and a significant delay in the onset of tumorigenesis (Fig. 1B
). Resveratrol treatment also significantly reduced tumor multiplicity (tumors/mouse), measured as a function of time, compared with UVB alone group (Fig. 1C
). Post-treatment of resveratrol was found to impart equal, if not better, protection than pretreatment. This suggests the observed effects of resveratrol are not through a sunscreen mechanism; rather, it is absorbed into the skin and activates a protective signaling cascade. Close histological examination of the tumors and skin of the animals by a board-certified dermatopathologist revealed that UVB exposure resulted in a variety of tumors including squamous cell carcinoma (SCC), Bowen’s disease, invasive carcinomas in situ, and actinic keratoses (AK). However, in the resveratrol-treated group (pre- and post-treatments), a majority of lesions were identified to be AKs with or without inflammation. This suggested that resveratrol might be inhibiting the malignant conversion of premalignant conditions such as actinic keratoses. More detailed studies are needed to firmly establish this hypothesis.
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2. Resveratrol protects the skin from UVB-mediated damages via modulating the expression and function of survivin
Sunlight-induced cancer develops as a result of a complex cascade of events initiated by chromosomal alterations and mutations. Because survivin is a critical regulator of survival/death of cells and its overexpression has been implicated in several cancers, we evaluated its involvement during chemoprevention of UVB-mediated skin carcinogenesis by resveratrol. Western blot and real-time PCR analyses demonstrated an appreciable overexpression in the levels of survivin in skin tumors (at protein and mRNA levels) whereas treatment of skin with resveratrol resulted in a down-modulation in protein and mRNA levels of survivin (Fig. 2
).
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Studies have shown that inhibition of melonoma tumor growth in vivo by deregulation of survivin or with chemotherapy may be useful in treating melanoma. Survivin expression has been found to prevent papilloma regression and promote conversion to SCC. Our results represent a novel finding that resveratrol may protect the skin from UVB-mediated damages including skin cancer development via modulating the expression and function of survivin.
To examine the mechanism of the observed modulation in survivin by UVB and/or resveratrol treatments, we determined the effect of these treatments on survivin phosphorylation at Thr34. Our data demonstrated that the level of survivin phosphorylation at Thr34 is up-regulated in UVB-induced tumors. Pre- and post-treatment of skin with resveratrol resulted in an appreciable down-regulation of survivin phosphorylation at Thr34. We believe that the observed resveratrol-caused decrease in survivin could be mediated via a decreased phosphorylation of this IAP protein at Thr34.
Studies have also suggested that a direct interaction between survivin and Smac/DIABLO is essential for the antiapoptotic activity of survivin. It was shown that a point mutation (D71R) in the baculovirus IAP repeat motif and a C-terminal deletion mutant (Surv-BIR) of survivin failed to bind to Smac/DIABLO and abrogate its ability to inhibit apoptosis. Thus, the N-terminal of mature Smac/DIABLO was suggested to be required for the function of survivin. We next determined the effect of UVB and/or resveratrol treatments on modulations in Smac/DIABLO protein in epidermal tissues and tumors in SKH-1 hairless mice. Our data demonstrated that Smac/DIABLO levels are significantly down-regulated in UVB-induced tumors; treatment of skin with resveratrol reversed this response. Our present observation suggesting an involvement of survivin and associated events during chemoprevention of UVB exposure-mediated skin carcinogenesis is supported by our recent studies showing that short-term UVB exposure resulted in a significant up-regulation in protein and/or mRNA levels of survivin and phospho-survivin with a concomitant decrease in Smac/DIABLO in mouse skin, both in vitro (in normal human epidermal keratinocytes) and in vivo (in SKH-1 hairless mouse skin).
It has been shown that during tumorigenesis, survivin expression is inversely correlated with apoptosis inhibition and positively correlated with proliferation and angiogenesis. We determined the involvement of apoptosis during resveratrol-mediated chemoprevention of skin tumorigenesis using M30 CytoDEATH detection kit that recognizes a specific caspase cleavage site within cytokeratin 18. We found a modest induction of apoptosis in UVB- induced mouse skin tumors. However, resveratrol (pre- and post-treatments) resulted in an enhancement in the induction of apoptosis, suggesting that the chemopreventive effects of resveratrol against UVB-induced skin tumorigenesis are mediated by an apoptotic elimination of UVB-initiated (damaged precancerous cells) via modulations in survivin and other associated events.
CONCLUSIONS AND SIGNIFICANCE
Our study demonstrated for the first time that resveratrol imparts strong chemopreventive effects against UVB exposure-mediated skin carcinogenesis relevant to human skin cancers. We suggest that resveratrol protects against UVB exposure-mediated damages via inhibition of survivin-phosphorylation at Thr34, which results in a decrease in survivin that leads to an up-regulation of Smac/DIABLO. This series of events finally leads to an apoptotic death of damages/premalignant or malignant cells. A simplified depiction is shown in Fig. 3
. We believe that the chemopreventive effects of resveratrol against UVB-mediated damages, including skin carcinogenesis, are mediated at least in part via modulations in the survivin pathway, but the possibility of involvement of other signaling events in observed chemopreventive effects of resveratrol is intriguing. It is conceivable to design resveratrol-containing emollient or patch as well as sunscreen and skin care products to prevent skin cancer as well as other conditions.
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FOOTNOTES
To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.04-3582fje; doi: 10.1096/fj.04-3582fje
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