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 microM) or bryostatin 1 (0.1 microM). 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 PKC alpha and-beta, novel PKC delta, atypical PKC zeta and-iota, and novel/atypical PKC mu. A decrease in cPKC alpha and-beta and an increase in nPKC delta were associated with the cDDP-resistant phenotype. The abundance of aPKC zeta or-iota was unaffected. H69/ VP-16 cells also displayed a reduction in cPKC beta and an increase in nPKC delta. 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.
Basu
A
A
Department of Pharmacology, University of Pittsburgh, Pennsylvania 15261, USA. anb@prophet.pharm.pitt.edu
Weixel
K
K
Saijo
N
N
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001761:Bleomycin / Q000494:pharmacology; D054713:Bryostatins; D002277:Carcinoma / Q000201:enzymology; D018288:Carcinoma, Small Cell / Q000201:enzymology*; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D006258:Head and Neck Neoplasms / Q000201:enzymology; D017405:Herpes Simplex Virus Protein Vmw65; D006801:Humans; D007783:Lactones / Q000494:pharmacology; D008175:Lung Neoplasms / Q000201:enzymology*; D018942:Macrolides; D010051:Ovarian Neoplasms / Q000201:enzymology; D017239:Paclitaxel / Q000494:pharmacology; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D054713:Bryostatins; D017405:Herpes Simplex Virus Protein Vmw65; D007783:Lactones; D018942:Macrolides; D001761:Bleomycin; D015240:Phorbol 12,13-Dibutyrate; C046785:bryostatin 1; D005047:Etoposide; D011493:Protein Kinase C; D017239:Paclitaxel; D002945:Cisplatin