Induction of Senescence in Diterpene Ester–Treated Melanoma Cells via Protein Kinase C–Dependent Hyperactivation of the Mitogen-Activated Protein Kinase Pathway

摘要: The diterpene ester PEP005 is a novel anticancer agent that activates protein kinase C (PKC) and induces cell death in melanoma at high doses. We now describe the vitro cytostatic effects of phorbol 12-myristate 13-acetate, observed 20% human lines. Primary cultures normal neonatal fibroblasts were resistant to growth arrest, indicating potential for tumor selectivity. Sensitive lines induced senesce exhibited G(1) G(2)-M arrest. There was sustained expression p21(WAF1/CIP1), irreversible dephosphorylation retinoblastoma protein, transcriptional silencing E2F-responsive genes sensitive Activation mitogen-activated (MAP)/extracellular signal-regulated (ERK) (MEK) 1/2 by PKC required ester-induced senescence. Expression profiling revealed MAP inhibitor HREV107 expressed higher transcript level compared with propose activation overstimulates RAS/RAF/MEK/ERK pathway, resulting molecular changes leading senescent phenotype.