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Staurosporine Induces Protein Kinase C Agonist Effects and Maturation of Normal and Neoplastic Mouse Keratinocytes in Vitro

Laboratory of Cellular Carcinogenesis and Tumor Promotion, Division of Cancer Etiology, National Cancer Institute, Bethesda, Maryland 20892

Staurosporine is a potent but nonselective inhibitor of protein kinase C (PKC) and blocks responses to 12-O-tetradecanoylphorbol-13-acetate (TPA) in several cell types in vitro. In cultured primary mouse keratinocytes, however, staurosporine fails to inhibit TPA-mediated keratinocyte maturation and itself elicits responses that are similar to TPA (T. Sako et al., Cancer Res., 48: 4646–4650, 1988). After exposure to 10 nM staurosporine for 24 h, essentially all keratinocytes undergo morphological differentiation, whereas 160 nM TPA induces this response in about 50% of epidermal cells. These concentrations of staurosporine and TPA cause a 4–5-fold induction of epidermal transglutaminase activity and cornified envelopes, both markers of the terminal stage of keratinocyte differentiation. Staurosporine, but not TPA, also induces morphological and biochemical maturation in 2 neoplastic mouse keratinocyte cell lines, 308 and SP-1. The ability of staurosporine to elicit the same responses as TPA suggested that it may be functioning paradoxically as a PKC agonist in intact keratinocytes. In support of this hypothesis, staurosporine induces ornithine decarboxylase activity, inhibits ¹²⁵I-labeled epidermal growth factor binding, and induces expression of c-fos mRNA. Downregulation of PKC by pretreatment of primary keratinocytes with 60 nM bryostatin partially blocks staurosporine-mediated induction of cornified envelopes and inhibition of ¹²⁵I-labeled epidermal growth factor binding, implicating PKC in these responses. The ability of staurosporine to mimic and/or enhance certain responses to TPA suggests that this agent is acting as a functional PKC agonist in cultured keratinocytes.

¹ Recipient of a Physician's Research Training Fellowship (PRTF-98) from the American Cancer Society.

² To whom requests for reprints should be addressed, at Laboratory of Cellular Carcinogenesis and Tumor Promotion, Division of Cancer Etiology, National Cancer Institute, Building 37/Room 3B25, Bethesda, MD 20892.

Received 3/26/91. Accepted 6/14/91.

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