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 Mice.

The study investigated the role of protein kinase Cepsilon (PKCepsilon) in the development of metastatic squamous cell carcinoma (mSCC) in transgenic mice. It was found that PKCepsilon overexpression in these mice led to increased tumor necrosis factor-alpha (TNFalpha) levels during skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA). This increase was linked to the development of mSCC. The study demonstrated that TPA-induced TNFalpha shedding was mediated by the TNF-alpha converting enzyme (TACE) and involved reactive oxygen species. Inhibiting TNFalpha synthesis with pentoxifylline prevented mSCC development, suggesting that PKCepsilon activation and subsequent TNFalpha shedding played a crucial role in tumor progression.