Characterization of the protein kinase C signal transduction pathway in cisplatin-sensitive and -resistant human small cell lung carcinoma cells

Protein kinase C (PKC) influences cellular sensitivity to cis- diamminedichloroplatinum(II) (cDDP). We have investigated whether the PKC signal transduction pathway is affected during the development of cellular resistance to cDDP. Activators of PKC, such as phorbol 12,13-dibutyrate (PDBu), enhanced the sensitivity of human small cell lung cancer H69 cells to cDDP by 2-fold but had no effect on the sensitivity of cDDP-resistant H69 cells (H69/CP) to cDDP. The maximum sensitization was achieved with 10 nM PDBu and blocked by down-regulation of PKC with higher concentrations of PDBu (1 μM) or bryostatin 1 (0.1 μM). PKC activity was decreased significantly in H69/CP cells compared to the drug-sensitive variant. A similar reduction in PKC activity was noted in ovarian carcinoma 2008 cells that were resistant to cDDP. A modest decrease in PKC activity was also observed in etoposide- resistant H69 (H69/VP-16) cells but not in Taxol-resistant H69 cells or bleomycin-resistant human head and neck carcinoma A-253 cells. H69 cells expressed conventional PKCα and -β, novel PKCδ, atypical PKCζ and -t, and novel/atypical PKCμ. A decrease in cPKCα and -β and an increase in nPKCδ were associated with the cDDP-resistant phenotype. The abundance of aPKCζ or -L was unaffected. H69/VP-16 cells also displayed a reduction in cPKCβ and an increase in nPKCδ. Taxol-resistant H69 cells had no alteration in the expression of any of the PKC isozymes. Thus, a reduction in cPKCs and an increase in nPKC may be associated with cDDP resistance.