Inhibition of the notch signaling pathway overcomes resistance of cervical cancer cells to paclitaxel through retardation of the epithelial-mesenchymal transition process.

Abstract

Use of paclitaxel as monotherapy or in combination with other therapeutic agents is a widely employed front-line chemotherapeutic strategy for cervical cancer. However, previous reports have shown that approximately 70% of the patients with cervical cancer develop resistance to paclitaxel. Epithelial-mesenchymal transition (EMT) contributes to the occurrence of chemoresistance in several types of cancer, including cervical cancer. Identification of the critical signaling pathway that regulates the EMT process may provide a novel strategy for avoiding or delaying the emergence of paclitaxel resistance during the treatment of cervical cancer. Herein, we established a paclitaxel-resistant cervical cancer cell line (HeLa-229PTR cells) by culturing parental HeLa-229 cells with increasing concentrations of paclitaxel. We observed elevated expression of Notch1 in HeLa-229PTR cells compared with their parental HeLa-229 cells, indicating its potential involvement in the EMT phenotype of the paclitaxel-resistant cells. Furthermore, silencing of the NOTCH1 gene, as well as treatment with a γ-secretase inhibitor (DAPT) partially reversed the EMT phenotype and significantly enhanced the sensitivity of HeLa-229PTR cells to paclitaxel. Moreover, we found that DAPT could significantly inhibit invasiveness, reduce colony formation activity, and promote apoptosis of HeLa-229PTR cells. Taken together, these results indicated that HeLa-229PTR cells develop the EMT phenotype partly through activation of Notch1 signaling. Thus, inhibition of Notch1 signaling can be a strategy for the reversal of the EMT phenotype and may increase the sensitivity of cervical cancer cells to treatment with paclitaxel.