Inhibition of tyrosine kinase Src suppresses pancreatic cancer invasiveness.
BACKGROUND
Src is a 60-kDa tyrosine kinase that plays a critical role in signal transduction associated with cell-extracellular matrix interactions. We tested the hypothesis that Src inhibition might suppress pancreatic cancer cellular invasiveness.


METHODS
We tested the effects of pyrazolopyrimidine (a Src kinase-specific inhibitor) on 3 human pancreatic cancer cell lines: BXPC-3, MIAPaCa-2, and PANC-1. Src expression was assayed with Western blotting. Pyrazolopyrimidine-mediated inhibition of Src phosphorylation was confirmed by immunoprecipitation. Matrix metalloproteinase (MMP) activities and cellular invasive potential were assessed by use of zymography and Boyden chamber assays, respectively. Cell growth was assessed with the MTT assay.


RESULTS
Src was expressed in all 3 pancreatic cancer cell lines tested. Pyrazolopyrimidine completely suppressed Src phosphorylation, inhibited MMP2 (72kDa) and MMP9 (92kDa) activities by 40% to 34% (P <.05), and suppressed cellular invasiveness by more than 90% (P <.05) in all 3 cell lines. Pyrazolopyrimidine had variable effects on cell growth: 50% reduction (P <.05) in BXPC-3, 7% reduction (P >.05) in MIAPaCa-2, and 22% reduction (P <.05) in PANC-1.


CONCLUSIONS
Inhibition of Src signaling results in a marked reduction of pancreatic cancer cellular invasiveness. Src may represent a novel therapeutic target for this deadly cancer.
Ito
Hiromichi
H
Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Gardner-Thorpe
James
J
Zinner
Michael J
MJ
Ashley
Stanley W
SW
Whang
Edward E
EE
D002455:Cell Division / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; C118531:pyrazolopyridine; D016392:Proto-Oncogene Proteins pp60(c-src)