Differential Down-Regulation of Epidermal Protein Kinase C by 12–O-Tetradecanoylphorbol-13-acetate and Diacylglycerol: Association with Epidermal Hyperplasia and Tumor Promotion

Laura A. Hansen, Nancy A. Monteiro-Riviere, Robert C. Smart

Research output: Contribution to journalArticle

95 Scopus citations

Abstract

A single topical application of 2 nmol 12–0-tetradecanoylphorbol-13-acetate (TPA) to CD-I mouse skin resulted in a rapid decrease in cytosolic, particulate, and total epidermal protein kinase C (PKC) activity at 6 h, which remained decreased by 70% at 96 h. This dose of TPA produced epidermal hyperplasia as determined by an increase in the number of nucleated epidermal cell layers. A single application of 10 γmol sn-l,2-didecanoylglycerol, a model 5ii-l,2-diacylglycerol and complete tumor promoter, induced ornithine decarboxylase to an extent similar to that of 2 nmol TPA. However, sn-l,2-didecanoylglycerol produced an 80% increase in particulate PKC activity that was accompanied by a 45% decrease in cytosolic PKC activity, resulting in no net change in total PKC activity. Unlike TPA, this dose of wi-l,2-dideca-noylglycerol did not produce a hyperplastic response. Additional dosing regimens were examined to determine whether the down-regulation of particulate PKC activity was associated with hyperplasia and tumor promotion. A tumor-promoting dosing regimen consisting of multiple applications of 5 or 10 Mmol sii-l,2-didecanoylglycerol twice daily for 1 week resulted in more than a 60% decrease in cytosolic and particulate PKC activity and a marked epidermal hyperplasia. Twice-weekly application of 10 Mmol 5if-l,2-didecanoylglycerol, a nonpromoting dosing rate, for 1 week decreased cytosolic PKC activity but increased particulate PKC activity and did not produce hyperplasia. Dosing regimens utilizing multiple applications of TPA decreased both particulate and cytosolic PKC activity and were also hyperplastic. PKC activity was also measured in epidermal papillomas from mice initiated with 7,12-dimethylbenz|a|-anthracene and promoted with either 5n-l,2-didecanoylglycerol or TPA. Cytosolic- and particulate-associated PKC activity in these papillomas was decreased by at least 70% and 40%, respectively, when compared with epidermis and whole skin. After 2 months without promoter treatment, both cytosolic and particulate PKC activity remained decreased in the papillomas, whereas epidermal PKC activity returned to control values by 2 to 3 weeks following cessation of several weeks of TPA treatment. Collectively, these data demonstrate that the down-regulation of epidermal PKC is associated with and may be a permissive event for epidermal hyperplasia and tumor promotion.

Original languageEnglish
Pages (from-to)5740-5745
Number of pages6
JournalCancer Research
Volume50
Issue number18
Publication statusPublished - Oct 1 1990
Externally publishedYes

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All Science Journal Classification (ASJC) codes

  • Cancer Research
  • Oncology

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