DKK1 Promotes Epithelial-Mesenchymal Transition and Cisplatin Resistance in Gastric Cancer via Activation of the PI3K/AKT Pathway.

Abstract

Chemotherapy is a classical method of cancer treatment. Cisplatin-based chemotherapy is a traditional and essential therapeutic approach in gastric cancer treatment. However, the development of drug resistance during treatment is a major obstacle that limits their further application, and molecular changes have occurred in the development of drug resistance. Here, we found that Dickkopf-related protein 1 (DKK1) is highly expressed in gastric cancer and related to poor prognosis in gastric cancer patients through public database mining. Next, we also identified that DKK1 is highly expressed in CDDP-resistant gastric cancer cell lines, supporting the notion that DKK1 is a necessary regulator of CDDP resistance. In terms of mechanistic research, our data reveal that DKK1 was able to activate the PI3K/AKT pathway and affect epithelial-to-mesenchymal transition, further contributing to CDDP resistance. Genetic knockdown and pharmacological inhibition of DKK1 recovered CDDP sensitivity both in vitro and in vivo. Therefore, our study highlights the potential of targeted inhibition of DKK1 to reverse CDDP resistance and alleviate metastatic properties in gastric cancer.