Abstract
2659
The PKC family of serine-threonine kinases has been widely implicated in the control of cell proliferation, with positive or negatives effects depending of the cell type and the relative expression of PKC isozymes. A clear link between PKC and cell cycle regulators has emerged in recent years, but the role of the PKCs in the different phases of the cell cycle are poorly understood. Here we show that in H358 lung cancer cells synchronized in the S phase using hydroxyurea, the PKC activator phorbol 12-myristate 13-acetate (PMA) dose-dependently induces a delay in the S-G2/M transition followed by cell cycle arrest both in G1 and G2/M phases, but it does not cause apoptosis. PMA also induces drastic morphological changes, as cells are flattened and enlarged, with increased cytoplasmic granulation, vacuolization, and in many cases become polynuclear. PMA also causes an elevation in SA-beta-Gal activity, a marker of senescence. PMA treatment increases the levels of the cdk inhibitor p21 and leads to the dephosphorylatyon of AKT, effects that are blocked by the pan-PKC inhibitor GF109203X and the PKCα specific inhibitor Gö6976. Moreover p21 depletion using RNAi blocks cell cycle arrest induced by PMA. We hypothesize that activation of PKCα during the S phase induces replicative senescence in H358 cells.
[Proc Amer Assoc Cancer Res, Volume 47, 2006]