Knockdown of CREB3L4 Inhibits Autophagy and Reduces Cisplatin Resistance in Gastric Cancer Cells by Downregulating BAG3.

Cisplatin resistance remains a major obstacle in the treatment of gastric cancer (GC), and autophagy has been increasingly recognized as a key cytoprotective mechanism contributing to chemoresistance. CREB3L4 is an endoplasmic reticulum membrane-bound transcription factor that has been shown to regulate the expression of Bcl-2 associated athanogene 3 (BAG3), a co-chaperone protein involved in autophagy and survival signaling in various cancers. However, whether the CREB3L4/BAG3 axis regulates autophagy and contributes to cisplatin resistance in gastric cancer cells remains unclear. In the present study, we investigated the roles of CREB3L4 and BAG3 in cisplatin-resistant GC cell lines and found that CREB3L4 and BAG3 were overexpressed. Furthermore, BAG3 expression was inhibited following CREB3L4 knockdown in gastric cancer cells. Notably, knockdown of CREB3L4 inhibited autophagy and alleviated cisplatin resistance in gastric cancer cells by down-regulating BAG3. In addition, silencing of CREB3L4 promoted apoptosis and inhibited cell proliferation, which was also associated with decreased BAG3 expression. Taken together, these findings indicate that depletion of CREB3L4 suppressed autophagy and reduced cisplatin resistance in GC cells by downregulating BAG3.