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

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 (PKC), 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 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 transgenic mice elicit elevated serum tumor necrosis factor (TNF) 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 and more than a 6-fold increase in ectodomain shedding of TNF into the serum of PKC transgenic mice relative to their wild-type littermates. Furthermore, this TPA-stimulated TNF shedding was proportional to the level of expression of PKC in the epidermis. Using the TNF- converting enzyme (TACE) inhibitor, TAPI-1, TPA-stimulated TNF shedding could be completely prevented in PKC transgenic mice and isolated keratinocytes. These results indicate that PKC signal transduction pathways to TPA-stimulated TNF ectodomain shedding are mediated by TACE, a transmembrane metalloprotease. Using the superoxide dismutase mimetic CuDIPs and the glutathione reductase mimetic ebselen, TPA-stimulated TNF shedding from PKC transgenic mice could be completely attenuated, implying the role of reactive oxygen species. Finally, i.p. injection of a TNF synthesis inhibitor, pentoxifylline, during skin tumor promotion completely prevented the development of mSCC in PKC transgenic mice. Taken together, these results indicate that: (a) PKC activation is an initial signal in TPA-induced shedding of TNF from epidermal keratinocytes; (b) PKC-mediated signals to TACE are possibly mediated through reactive oxygen species; and (c) TPA-induced TNF shedding may play a role in the development of mSCC in PKC transgenic mice.

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