Integrin α5 promotes migration and cisplatin resistance in esophageal squamous cell carcinoma cells.

Cisplatin, as one of the front-line chemotherapeutic drugs, is employed for the treatment of esophageal squamous cell carcinoma (ESCC). However, the occurrence of cisplatin resistance and metastasis remain as challenges in clinical therapy. To investigate the mechanism involved in cisplatin resistance, in this study, we established cisplatin resistant cell lines (Res) from Eca109 and TE-1 parental cells (Par), and we observed that fibronectin (FN)-mediated cell migration and spreading abilities are significantly increased in Res cells when compared to Par cells. Furthermore, we found that the integrin α5 expression is remarkably upregulated in Res cells, and inhibition of α5 results in more apoptosis and endows the Res cells resensitize to cisplatin in vitro and in vivo. In a mechanistic manner, we identified the expression of BARD1 is significantly increased in Res cells, and silencing of BARD1 reverse the effects of α5 on cisplatin resistance. Moreover, we found that the α5/FAK/PI3K/AKT signal axis is activated in Res cells, which mediates the increased expression of BARD1, as well as the cisplatin resistance and cell survival. Thus, our results demonstrate that α5 is required for cisplatin resistance through the promotion of FAK/PI3K/AKT/BARD1 signaling to prevent cells from apoptosis and enhance the DNA damage repair ability. Taken together, our study provides plausible mechanisms of α5-mediated cisplatin resistance in ESCC cells, highlighting that inhibition of α5 may be a potential target for improving efficacy in cisplatin-based chemotherapy. AJCR