Overcoming paclitaxel resistance via PI3K pathway mediated stathmin1 regulation in gastric cancer

Abstract

The major obstacle to successful treatment of gastric cancer is chemoresistance. Targeted therapies in combination with chemotherapy would provide promising results in the treatment of patients with gastric cancer, potentially overcoming chemoresistance. Our study was designed to investigate the influence of PI3K pathway mediated stathmin1 on paclitaxel susceptibility in gastric cancer cell lines.Sensitivity to paclitaxel was highly correlated with the protein level of stathmin 1 expression in six gastric cancer cell lines. Knock-down of stathmin1 with siRNA in SNU-1, SNU-5, and SNU-16 cell lines resulted in the partial reversal of paclitaxel resistance. Pre-treatment of gastric cancer cells with LY294002, a PI3K inhibitor, attenuated cell’s resistance to paclitaxel. Of note, PI3K inhibitor pretreatment also promoted the down regulation of stathmin1 expression.Our results suggested that stathmin1 expression in tumor tissues could be exploited as not only a potential predictive marker for paclitaxel susceptibility but also a therapeutic target to overcome drug resistance. Further PI3K pathway might plays an important role in paclitaxel chemoresistance on gastric cancer cells by upregulating downstream effector stathmin1. Therefore PI3K inhibitor could salvage the paclitaxel treatment in gastric cancer patients with high stathmin1 expression thereby improving the clinical outcome of patients with gastric cancer.