Overcoming gemcitabine resistance through oncolytic adenovirus expressing TRAIL/shHSP27 in pancreatic cancer cells

Abstract

According to previous studies, TRAIL-induced activation of Akt catalytic activity and phosphorylation are highly correlated with p38/HSP27 phosphorylation; moreover, the phosphorylation of p38/HSP27 increases further during incubation with curcumin and TRAIL, which induces significant apoptotic cell death in DU-145 cells. Furthermore, the cellular levels of phosphorylated HSP27 reportedly act as a determinant of cell fate: from cell survival to cell death in a biphasic manner in the presence of the anticancer agent gemcitabine, an antitumor drug currently used for the treatment of advanced pancreatic cancer. Gemcitabine also induces p38/HSP27 phosphorylation and acquired resistance at lower concentrations, similar to TRAIL. In the present study, after the acquisition of gemcitabine resistance, cancer cells (DU-145 or MiaPaCa-2) expressed greater NF-κB activity. However, the NF-κB activity, as well as colony formation, in gemcitabine-resistant cells was significantly decreased by HSP27 downregulation and subsequent TRAIL treatment. This phenomenon was clearly seen in pancreatic cancers with K-ras mutation, especially when HSP27 downregulation was combined with gemcitabine and TRAIL treatment, suggesting HSP27 plays an essential role in K-ras oncogene signaling cascade. In conclusion, HSP27 silencing may provide a new potential strategy for overcoming drug resistance and ultimate metastasis in pancreatic cancer cells with K-ras mutation.