S-Phase-specific Activation of PKCα Induces Senescence in Non-small Cell Lung Cancer Cells

• Published in: The Journal of biological chemistry 2008-02, Vol.283 (9), p.5466-5476
• Main Authors: Oliva, Jose L., Caino, M. Cecilia, Senderowicz, Adrian M., Kazanietz, Marcelo G.
• Format: Article
• Language: English
• Subjects: beta-Galactosidase - genetics; beta-Galactosidase - metabolism; Carcinogens - pharmacology; Carcinoma, Non-Small-Cell Lung - enzymology; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Cell Cycle - drug effects; Cell Line, Tumor; Cellular Senescence - drug effects; Cellular Senescence - genetics; Cyclin-Dependent Kinase Inhibitor p21 - biosynthesis; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Enzyme Activation - drug effects; Enzyme Activation - genetics; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - genetics; Humans; Isoenzymes - genetics; Isoenzymes - metabolism; Protein Kinase C-alpha - genetics; Protein Kinase C-alpha - metabolism; Protein Kinase C-delta - genetics; Protein Kinase C-delta - metabolism; S Phase - drug effects; S Phase - genetics; Telomerase - genetics; Telomerase - metabolism; Tetradecanoylphorbol Acetate - pharmacology; Up-Regulation - drug effects; Up-Regulation - genetics
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M707576200

Protein kinase C (PKC) has been widely implicated in positive and negative control of cell proliferation. We have recently shown that treatment of non-small cell lung cancer (NSCLC) cells with phorbol 12-myristate 13-acetate (PMA) during G1 phase inhibits the progression into S phase, an effect mediated by PKCδ-induced up-regulation of the cell cycle inhibitor p21Cip1. However, PMA treatment in asynchronously growing NSCLC cells leads to accumulation of cells in G2/M. Studies in post-G1 phases revealed that PMA induced an irreversible G2/M cell cycle arrest in NSCLC cells and conferred morphological and biochemical features of senescence, including elevated SA-β-Gal activity and reduced telomerase activity. Remarkably, this effect was phase-specific, as it occurred only when PKC was activated in S, but not in G1, phase. Mechanistic analysis revealed a crucial role for the classical PKCα isozyme as mediator of the G2/M arrest and senescence, as well as for inducing p21Cip1 an obligatory event for conferring the senescence phenotype. In addition to the unappreciated role of PKC isozymes, and specifically PKCα, in senescence, our data introduce the paradigm that discrete PKCs trigger distinctive responses when activated in different phases of the cell cycle via a common mechanism that involves p21Cip1 up-regulation.