Inhibition of Src reduces gemcitabine-induced cytotoxicity in human pancreatic cancer cell lines

• Published in: Cancer letters 2008-02, Vol.260 (1), p.155-162
• Main Authors: Ichihara, Naoto, Kubota, Yoshitsugu, Kitanaka, Akira, Tanaka, Terukazu, Taminato, Tomohiko
• Format: Article
• Language: English
• Subjects: Antimetabolites, Antineoplastic - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Apoptosis; Apoptosis - drug effects; Biomedical research; Cancer therapies; Cell culture; Cell growth; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Culture Media - metabolism; Cytotoxicity; Deoxycytidine - administration & dosage; Deoxycytidine - analogs & derivatives; Dose-Response Relationship, Drug; Gemcitabine; Hematology, Oncology and Palliative Medicine; Humans; Kinases; Medical prognosis; Mutation; Pancreas; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - enzymology; Pancreatic Neoplasms - pathology; Phosphorylation; PP2; Protein Kinase Inhibitors - administration & dosage; Proteins; Pyrimidines - administration & dosage; Rodents; Serum - metabolism; Signal Transduction - drug effects; Src; src-Family Kinases - antagonists & inhibitors; src-Family Kinases - genetics; src-Family Kinases - metabolism; Transfection
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2007.10.035

Abstract In the present study, we examined the role of Src in gemcitabine-induced cell growth suppression in human pancreatic cancer cell lines. In two human pancreatic cancer cell lines, PK-9 and MIA PaCa-2, we found that a selective Src protein tyrosine kinase inhibitor, PP2, inhibited gemcitabine-induced cell growth suppression. When dominant negative src cDNA was constitutively expressed in PK-9 cells (PK-9-Src-DN), the degree of gemcitabine-induced cell growth suppression was decreased compared with that of mock-transfected PK-9 cells. The mechanism of the inhibitory effect of gemcitabine-induced cytotoxicity was found to be the suppression of apoptosis, which was downregulated in PK-9-Src-DN cells. These results indicate that Src mediates signals that culminate in suppressing cell growth and survival in the presence of gemcitabine, at least in particular cell lines.