Abstract 4875: Topically applied Hsp90 inhibitor 17-(allylamino)-17-demethoxygeldanamycin inhibits ultraviolet radiation-induced development of cutaneous squamous cell carcinomas.

Abstract

Abstract Skin cancer is the second most common malignancy encountered in the U.S. with an expected diagnosis of 1.3 million new cases of non-melanoma skin cancer each year. Cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) are the most common non-melanoma forms of human skin cancer. SCC, unlike BCC, invades the nearby tissues. SCC is mainly caused by cumulative ultraviolet radiation (UVR) exposure over the course of a lifetime. Certain vulnerable populations, e.g., organ transplant recipients, have extraordinarily high rates of SCC (>50%) with markedly worse morbidity and mortality. To date, there are no accepted criteria for defining or managing these SCC patients. We found that PKCε is an important component of UVR-induced signal transduction pathways to the development of SCC. Also, PKCε is expressed in human and mouse SCC. To find clues about the mechanism by which PKCε may impart susceptibility to UVR-induced development of SCC, we found that PKCε interacts with Hsp90β. In this experiment, PKCε transgenic mice were exposed once to a UVR (4 kJ/m2). PKCε-Hsp90 interaction was analyzed, by co-immunoprecipitation and Western blotting, at 1 and 2hr post UVR treatment. PKCε- Hsp90β interaction appears to be enhanced as early as 1hr post UVR treatment. The co-localization of PKCε with Hsp90β was observed in mouse epidermis, UVR-induced SCC in SKH-1 hairless mice and human SCC. Topical application of Hsp90 inhibitor 17-(allylamino)-17-demethoxygeldanamycin (17AAG) to mice inhibited UVR-induced Hsp90β-PKCε interaction, decreased PKCε expression levels and inhibited UVR-induced development of SCC. To determine the effects of topical 17AAG on UVR-induced development of SCC, the SKH1 hairless mice (6-7 week old) were exposed to UVR. The UVR source was Kodacel- filtered FS-40 sun lamps (approximately 60% UVB and 40% UVA). Mice were exposed to UVR (1.8 kJ/m2) three times weekly (Monday, Wednesday and Friday). The mice in the vehicle group (n=18) received topical treatment of 200μl vehicle (DMSO: acetone: 1:40 v/v) before and after UVR exposures. The mice in treatment group (n=13) received freshly prepared 500nmol of 17AAG (DMSO: acetone: 1:40 v/v) before and after UVR exposure. Topical 17AAG decreased SCC latency by 17 weeks and significantly (P<0.001) inhibited SCC incidence. 17AAG-caused inhibition of UVR-induced SCC accompanied inhibition of UVR-induced hyperplasia, Hsp90β and PKCε expression levels. Interestingly, 17AAG-caused inhibition of UVR-induced Hsp90β accompanied an increase in Hsp70 protein level. These results led us to conclude that disruption of UVR-induced interaction of Hsp90β with PKCε and other oncogenic client proteins by Hsp90 inhibitor 17AAG may result in prevention and treatment of UVR-induced SCC. (Support: RO1CA102431). Citation Format: Anupama Singh, Samuel J. Bauer, Ashok Singh, Jordan M. Sand, Bilal B. Hafeez, Louise Meske, Ajit K. Verma. Topically applied Hsp90 inhibitor 17-(allylamino)-17-demethoxygeldanamycin inhibits ultraviolet radiation-induced development of cutaneous squamous cell carcinomas. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4875. doi:10.1158/1538-7445.AM2013-4875