siRNA directed against TrkA sensitizes human pancreatic cancer cells to apoptosis induced by gemcitabine through an inactivation of PI3K/Akt-dependent pathway
- Author:
Dapeng LIU
;
Yong ZHANG
;
Hong REN
;
Wuke CHEN
- Publication Type:Journal Article
- Keywords:
siRNA;
TrkA;
PI3K/Akt;
pancreatic cancer
- From:
Journal of Pharmaceutical Analysis
2007;19(1):101-106
- CountryChina
- Language:Chinese
-
Abstract:
Objective To determine the effect of suppressing TrkA expression on pancreatic cancer chemosensitivity to gemcitabine and further disclose the role of PI3K/Akt signal transduction pathway in pancreatic cancer chemoresistance. Methods Human pancreatic cancer cell lines PANC-1, MIA-PaCa-2 and ASPC-1 were studied. The expression and kinase activity of TrkA were determined by Western blot analysis and in vitro kinase assay, respectively. RNA interference was used to suppress TrkA expression. Gemcitabine-induced cytotoxicity was determined by tetrazolium reduction assay and caspase profiling was performed. The effect of TrkA-specific siRNA on PI3K/Akt activity was also quantified. Results TrkA expression and kinase activity in cell lines were directly correlated with gemcitabine chemoresistance. TrkA-specific siRNA suppressed TrkA expression and kinase activity, and furthermore increased gemcitabine-induced, caspase-mediated apoptosis. PI3K/Akt activity was decreased by suppression of TrkA expression. Conclusion TrkA is a determinant of pancreatic adenocarcinoma chemoresistance and PI3K/Akt is a key signaling component by which NGF activation of the TrkA signal transduction pathway protects pancreatic cancer cells from chemotherapy-induced cell death.
