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

SIMPLE SUMMARY: Dickkopf-related protein 1 (DKK1) plays different roles in different cancers, and its aberrant expression is associated with tumor progression and poor prognosis. However, the role of DKK1 in gastric cancer is not well studied or understood, especially regarding its function in gastric cancer chemoresistance. Chemotherapy is a fundamental treatment method for gastric cancer. Resistance to chemotherapy limits chemotherapeutic agents in clinical applications, and the mechanism of drug resistance needs to be elucidated. In this study, we found that DKK1 was highly expressed in gastric cancer patients and cisplatin (CDDP)-resistant cell lines. DKK1 was able to activate the PI3K/AKT pathway and affect epithelial-to-mesenchymal transition (EMT), further contributing to CDDP resistance. DKK1 inhibition recovered CDDP sensitivity both in vitro and in vivo. Therefore, our study highlights the potential targeted inhibition of DKK1 to reverse CDDP resistance and alleviate metastatic properties in gastric cancer. 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.