siRNA directed against c-Src enhances pancreatic adenocarcinoma cell gemcitabine chemosensitivity.
BACKGROUND
The c-Src tyrosine kinase is a determinant of malignant cellular behavior in a variety of human cancers. We sought to determine the effect of suppressing c-Src expression on pancreatic adenocarcinoma chemosensitivity to gemcitabine.


METHODS
PANC1, MIAPaCa2, BxPC3, and Capan2 pancreatic adenocarcinoma cell lines were studied. Expression of c-Src was determined by Western blot analysis. c-Src kinase activity was determined by in vitro kinase assay. RNA interference was used to suppress c-Src expression. Gemcitabine-induced cytotoxicity was determined by tetrazolium reduction assay and caspase profiling was performed. The effect of Src-specific siRNA on Akt activity was quantified.


RESULTS
Src expression and kinase activity in cell lines were directly correlated with gemcitabine chemoresistance. c-Src-specific siRNA suppressed c-Src expression and kinase activity. c-Src-specific siRNA increased gemcitabine-induced, caspase-mediated apoptosis. Akt activity was decreased by suppression of c-Src expression.


CONCLUSIONS
c-Src is a determinant of pancreatic adenocarcinoma chemoresistance and represents a potential target for therapeutic intervention.
Duxbury
Mark S
MS
Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Ito
Hiromichi
H
Zinner
Michael J
MJ
Ashley
Stanley W
SW
Whang
Edward E
EE
D000230:Adenocarcinoma / Q000188:drug therapy*; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D034741:RNA, Small Interfering / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D034741:RNA, Small Interfering; D003841:Deoxycytidine; D019061:src-Family Kinases; D000093542:Gemcitabine