Protein kinase C: a target for therapy in pancreatic cancer.
OBJECTIVE
Protein kinase C (PKC) is involved in tumor growth and apoptosis and hence represents a potential target for cancer therapy. This study investigated the expression of PKC in pancreatic tumor tissue in comparison to adjacent normal tissue and determined the modulation of PKC by bryostatin-1 (BRYO) on pancreatic cancer cell lines.


METHODS
Pancreatic tissue was obtained from 18 patients who had a resection (14 with ductal adenocarcinoma and 4 with adenoma and high-grade dysplasia). Cytosolic and nuclear membrane PKCs in the paired samples were determined by immunoblotting. HPAC cells were treated with gemcitabine and BRYO and in sequential and concomitant combination. To evaluate cell viability, apoptosis, and electrophoretic mobility shift assay, 3-(4,5-dimetylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, enzyme-linked immunosorbent assay, and nuclear factor kappaB (NF-kappaB) assays were used.


RESULTS
As compared with the adjacent normal tissue, PKC-alpha, PKC-beta1, and PKC-delta were higher in the tumor; PKC-epsilon was higher in the normal tissue. Pretreatment with gemcitabine followed by BRYO resulted in decreased cell viability, increased apoptosis, and inhibited NF-kappaB than either agent alone or BRYO followed by gemcitabine.


CONCLUSIONS
Protein kinase C is overexpressed and activated in pancreatic cancer as compared with normal tissue. Inhibition of PKC could sensitize pancreatic cancer cell lines to the effects of gemcitabine. The potentiation of gemcitabine by BRYO is sequence-dependent and mediated through inhibition of PKC-dependent activation of NF-kappaB.
El-Rayes
Bassel F
BF
Department of Hematology and Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA.
Ali
Shadan
S
Philip
Philip A
PA
Sarkar
Fazlul H
FH
D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D000236:Adenoma / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D054713:Bryostatins / Q000008:administration & dosage; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D012016:Reference Values; D000093542:Gemcitabine
D054713:Bryostatins; D007527:Isoenzymes; D047428:Protein Kinase Inhibitors; D003841:Deoxycytidine; C046785:bryostatin 1; D011493:Protein Kinase C; D000093542:Gemcitabine