Skin cancer constitutes ∼30% of all newly diagnosed cancers in the world and solar ultraviolet (UV) radiation, particularly its UVB component (290-320 nm), is its established cause. Exposure to UV radiation also leads to precancerous conditions and a variety of other adverse effects. A clear understanding of genetic controls of cellular proliferation and cell division may provide the basis for the rational design of specific targets and therapeutic strategies for the management of skin cancer. This study was designed to investigate our hypothesis that UVB exposure to skin, via modulating Polo- and Aurora- family kinases, causes mitotic catastrophe in skin cells that may contribute to the development of skin cancer and other hyperproliferative skin disorders. The Polo and Aurora families kinases are involved in the regulation of mitosis; and the overexpression of Aurora A, Aurora B, and Polo-like kinase 1 (Plk1) causes a variety of cell division defects. Plk1 and Aurora A have been found to be overexpressed in a variety of cancers and evidence suggests that Aurora B has a correlative link to carcinogenesis. Employing in vitro as well as in vivo models, we studied the effect of UVB exposure on modulations in Plk- and Aurora- kinases and other associated events. Our in vitro data demonstrated that UVB exposure (30 mJ/cm2) resulted in a significant time-dependent upregulation in the protein levels of Plk1, Aurora A and Aurora B in HaCaT keratinocytes. The observed induction of these important mitosis-regulatory molecules was associated with a significant i) blockade of cell cycle at G2/M phase, ii) induction of apoptosis, and iii) upregulation of cyclin B1 and cdc2, the important regulatory molecules in G2/M phase of the cell cycle. The relevance of our in vitro findings was assessed under in vivo situations where UVB exposure (180 mJ/cm2) to SKH-1 hairless mouse skin was found to result in a significant upregulation in the protein levels of Plk1, Aurora A and Aurora B in the epidermis. Further, similar to the in vitro findings, this upregulation in mitosis kinases was found to be associated with a significant increase in i) upregulation of cyclin B1 and cdc2, and ii) induction of apoptosis. Furthermore, our data also demonstrated a significant upregulation of protein levels of Plk1, Aurora A, Aurora B, cyclin B1 and cdc2 in UVB-mediated squamous cell carcinoma. Based on our study, we suggest that UVB exposure causes mitotic catastrophe in skin that may contribute to the development of cancer. Thus, our study demonstrated, for the first time, the important role of mitosis kinases Plk1, Aurora A and Aurora B (and the associated events) in the UVB response and UVB-mediated skin carcinogenesis. We suggest that ‘mitotic catastrophe’ could serve as a target for development of strategies for treatment/chemoprevention of skin cancer.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]