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[Cancer Research 63, 6547-6555, October 1, 2003]
© 2003 American Association for Cancer Research

Epidemiology and Prevention

Protein Kinase C{epsilon} Is Linked to 12-O-tetradecanoylphorbol-13-acetate-induced Tumor Necrosis Factor-{alpha} Ectodomain Shedding and the Development of Metastatic Squamous Cell Carcinoma in Protein Kinase C{epsilon} Transgenic Mice1

Deric L. Wheeler, Kristin J. Ness, Terry D. Oberley and Ajit K. Verma2

Departments of Human Oncology [D. L. W., K. J. N., A. K. V.] and Pathology and Laboratory Medicine [T. D. O.], Medical School, University of Wisconsin, Madison, Wisconsin 53792

Protein kinase C{epsilon} (PKC{epsilon}), a Ca2+-independent, phospholipid-dependent serine/threonine kinase, is among the PKC isoforms expressed in mouse epidermis. We reported that FVB/N transgenic mice that overexpress (~18-fold) PKC{epsilon} protein in basal epidermal cells and cells of the hair follicle develop papilloma-independent metastatic squamous cell carcinoma (mSCC) elicited by 7,12-dimethylbenz(a)anthracene-initiation and 12-O-tetradecanoylphorbol-13-acetate (TPA)-promotion protocol. We now present that PKC{epsilon} transgenic mice elicit elevated serum tumor necrosis factor (TNF){alpha} levels during skin tumor promotion by TPA, and this increase may be linked to the development of mSCC. A single topical application of TPA (5 nmol) to the skin, as early as 2.5 h after treatment, resulted in a significant (P < 0.01) increase (2-fold) in epidermal TNF{alpha} and more than a 6-fold increase in ectodomain shedding of TNF{alpha} into the serum of PKC{epsilon} transgenic mice relative to their wild-type littermates. Furthermore, this TPA-stimulated TNF{alpha} shedding was proportional to the level of expression of PKC{epsilon} in the epidermis. Using the TNF-{alpha} converting enzyme (TACE) inhibitor, TAPI-1, TPA-stimulated TNF{alpha} shedding could be completely prevented in PKC{epsilon} transgenic mice and isolated keratinocytes. These results indicate that PKC{epsilon} signal transduction pathways to TPA-stimulated TNF{alpha} ectodomain shedding are mediated by TACE, a transmembrane metalloprotease. Using the superoxide dismutase mimetic CuDIPs and the glutathione reductase mimetic ebselen, TPA-stimulated TNF{alpha} shedding from PKC{epsilon} transgenic mice could be completely attenuated, implying the role of reactive oxygen species. Finally, i.p. injection of a TNF{alpha} synthesis inhibitor, pentoxifylline, during skin tumor promotion completely prevented the development of mSCC in PKC{epsilon} transgenic mice. Taken together, these results indicate that: (a) PKC{epsilon} activation is an initial signal in TPA-induced shedding of TNF{alpha} from epidermal keratinocytes; (b) PKC{epsilon}-mediated signals to TACE are possibly mediated through reactive oxygen species; and (c) TPA-induced TNF{alpha} shedding may play a role in the development of mSCC in PKC{epsilon} transgenic mice.




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