Distinct protein kinase C isozymes signal mitogenesis and apoptosis in human colon cancer cells

Background & Aims: Protein kinase C (PKC) is a family of serine-threonine k inases that transmit signals from cell surface receptors. To determine if d istinct PKC isozymes transmit proliferative and/or apoptotic signals in col on cancer cells, we examined the effects of 3 PKC agonists, phorbol 12-myri state 13 acetate (PMA), ingenol 3,20-dibenzoate (IDB), and bistratene A, an d a selective PKC inhibitor, GF 109203X, on proliferation, apoptosis, and a ctivation of individual PKC isozymes in 5 colon cancer cell lines. Methods: Effects were assayed by a formazan-based colorimetric assay, [H-3]thymidin e incorporation, fluorescent nuclear staining, annexin V binding, DNA fragm entation assay, and immunoblotting of cytoplasmic and membrane fractions fo r PKC isozymes. Results: Two cell lines, SNU-C1 and SNU-C4, showed prolifer ative responses to PMA (0.1-1 nmol/L) and IDB (10-1000 nmol/L) and marked a poptotic responses to PMA (>5 nmol/L) and bistratene A (>1 mu mol/L). GF 10 9203X blocked proliferative and apoptotic effects of PMA with distinct IC(5 0)s. Proliferative concentrations of PMA and IDB caused translocation of PK C epsilon alone, whereas apoptotic concentrations of PMA and bistratene A i nduced translocation of PKC delta. Conclusions: Activation of PKC epsilon a nd PKC delta triggers proliferative and apoptotic signals, respectively, in SNU-C4 colon cancer cells. These 2 isozymes may play important opposing ro les in normal homeostasis and neoplastic transformation of the colorectal e pithelium.