Abstract 1591: Protein kinase Cε, which is linked to ultraviolet radiation-induced cutaneous damage and development of squamous cell carcinomas, associates with Hsp90β, a core component of multiprotein complex inolving several collaborating chaperones Hsp70/Hsp40, Hop/sti, Cdc37 and p21

Abstract

Abstract Chronic exposure to ultraviolet radiation (UVR) is the most common etiologic factor linked to the development of squamous cell carcinoma (SCC), a nonmelanoma form of skin cancer that can metastasize. We have reported that protein kinase C epsilon (PKCε) expression level dictates the susceptibility of mice to the development of SCC by UVR. As compared to wildtype littermates, PKCε over-expressing transgenic mice exhibit decreases in tumor latency by 12 weeks and a 3-fold increase in tumor multiplicity (Cancer Research, 64, 7756, 2004). To find clues about the mechanism by which PKCε may impart susceptibility to UVR-induced development of SCC, we found that PKCε interacts with heat shock protein (Hsp) 90β. Hsp90 is a ubiquitous molecular chaperone, which plays key roles in the folding, activation and assembly of a range of structurally and functionally different client proteins (e.g., telomerase, nuclear hormone receptors, protein kinases) in eukaryotic cells. Hsp90, a core component of multiprotein complex involving several collaborating chaperons (e.g., Hsp70/Hsp40, Hop/sti1, Cdc37, p21), exhibits a high degree of specificity towards client proteins. In the present experiments, mice were exposed to a single UVR (2 kJ/m2) treatment, emitted by Kodacel-filtered FS-40 sun lamps (approximately 60% UVB and 40% UVA). In reciprocal immunoprecipitation/blotting experiments, Hsp90β and its associated chaperons Hsp70 and p21 co-immunoprecipitated with PKCε in intact mouse epidermis in vivo. The association of PKCε with Hsp90β was further enhanced after UVR exposure of dorsal skin in both PKCε transgenic and wild-type mice. The association of PKCε with Hsp90β was significantly increased in PKCε over-expressing transgenic mice as compared to wild-type littermates. In summary, association of Hsp90 with its client PKC is essential for both its maturation into a signaling-competent enzyme and enzyme stability (JBC, 284: 4921, 2008). In UVR mouse skin carcinogenesis, association of Hsp90β with PKCε may be required for sustained PKCε activity. We have previously reported that PKCε interacts with Stat3, phosphorylates Stat3Ser727 and is essential for Stat3-regulated gene expression (Cancer Research, 67, 1385, 2007). PKCε overexpressing transgenic mice exhibits constitutive activation of Stat3 and increased susceptibility to SCC induction by UVR. Association of Hsp90 with PKCε may critical for these biological effects. We conclude that Hsp90, PKCε and Stat3 are potential molecular targets for human cancer prevention and treatment (Support: NIH grants CA102431, CA35368 and T32ES007015) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1591.