Inhibition of tyrosine kinase Src suppresses pancreatic cancer invasiveness.

Abstract

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. 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. 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. 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.