Inhibition of activated Stat3 reverses drug resistance to chemotherapeutic agents in gastric cancer cells

Multidrug resistance is a major obstacle in the treatment of gastric cancer. The underlying mechanisms of this phenomenon have not been well understood. Accumulating evidence indicates that Stat3 plays an important role in tumorigenesis of various primary cancers and cancer cell lines by upregulating cell survival proteins and downregulating tumor suppressors. We propose that the Stat3 pathway is also involved in acquired drug resistance of gastric cancer. To test this hypothesis, we investigated the expression and activation of Stat3 in drug resistant gastric cancer cell lines. Western blotting and real-time reverse transcription-PCR determined that Stat3 and its target genes were overactivated and/or overexpressed in drug resistant cells. Inhibition of Stat3 function resulted in significant decreases in cisplatin resistance and enhanced apoptosis in drug resistant cells. The levels of Stat3 target oncogenes such as Bcl-2 and c-Myc were decreased with DPP, a Stat3 inhibitor, treatment, while the expression of tumor suppressor p53 was increased. Interestingly, the vacuolar ATPase, a proton pump which interferes the uptake of therapeutic drugs, was down regulated by Stat3 inhibition. In conclusion, these data supported the hypothesis that interruption of Stat3 signaling could reverse resistance to chemotherapy agents in human gastric cancer cells. (C) 2011 Elsevier Ireland Ltd. All rights reserved.