The Involvement of Novel Protein Kinase C Isozymes in Influencing Sensitivity of Breast Cancer MCF-7 Cells to Tumor Necrosis Factor-alpha

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Vol. 53, Issue 1, 105-111, January 1998

The Involvement of Novel Protein Kinase C Isozymes in Influencing Sensitivity of Breast Cancer MCF-7 Cells to Tumor Necrosis Factor- $alpha$

Alakananda Basu

Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261

Protein kinase C (PKC) has been implicated in tumor necrosis factor- $alpha$ (TNF) signaling. Structurally and functionally distinctPKC activators and selective inhibitors of PKC were used to investigatethe involvement of PKC isozymes in influencing TNF sensitivityin MCF-7 cells. Activators of PKC, such as phorbol-12,13-dibutyrate(PDBu) (1.0 µM), indolactam V (10 µM), and bryostatin 1 (1.0 µM)decreased the sensitivity of MCF-7 cells to TNF by 5-, 10-, and1.7-fold, respectively. The PKC-specific inhibitor bisindolylmaleimideII (BIM) ( $>=$ 1 µM) antagonized the effect of PDBu in protectingMCF-7 cells against TNF cytotoxicity. High concentrations of BIM( $>=$ 10 µM) also significantly enhanced the sensitivity of MCF-7cells to TNF. In contrast, Gö 6976, a specific inhibitor of cPKCs,did not potentiate TNF sensitivity and failed to reverse the effectof PDBu. In addition, BIM but not Gö 6976 blocked PDBu-mediateddown-regulation of TNF receptors. There was no correlation betweendown-regulation of PKC $alpha$ , - $delta$ , and - $epsilon$ , and protection against TNFcytotoxicity by PKC activators. A 6-hr exposure to 1.0 µM PDBu,10 µM indolactam V, and 1.0 µM bryostatin 1 caused a 1.8-, 3.5-and 1.2-fold induction, respectively, of nPKC $eta$ in MCF-7 cells.Similar exposure to BIM but not Gö 6976 led to a significant down-regulationof nPKC $eta$ . This novel regulation of PKC $eta$ implicates this isozymein PDBu-mediated protection of MCF-7 cells against TNF cytotoxicity.

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