ZIPK activates the IL‐6/STAT3 signaling pathway and promotes cisplatin resistance in gastric cancer cells

Abstract

Gastric cancer is one of the most common malignant cancers globally. Chemotherapy resistance remains a major obstacle in the treatment of gastric cancer, and the molecular mechanisms underlying drug resistance are still not well understood. We previously reported that Zipper interacting protein kinase (ZIPK), also known as death‐associated protein kinase3, exerts an oncogenic effect on gastric cancer via activation of Akt/NF‐κB signaling and promotion of stemness. Here, we explored the roles of ZIPK in cisplatin resistance. We report that ZIPK enhances cell proliferation and invasion and reduces the antitumor activity of cisplatin in gastric cancer. In addition, our western blot data suggest that ZIPK activated the IL‐6/STAT3 signaling pathway. Furthermore, ZIPK increased the expression of IL‐6 and multidrug‐resistance genes. Using the STAT3 inhibitor stattic to block the IL‐6/STAT3 signaling pathway strongly increased the sensitivity of ZIPK‐expressed cells to cisplatin. In conclusion, ZIPK may play a role in cisplatin resistance through activation of the IL‐6/ STAT3 signaling pathway. Inhibition of STAT3 in gastric cancer overexpressing ZIPK might have potential to improve the efficacy of cisplatin.

Targeting Death-Associated Protein Kinases for Treatment of Human Diseases: Recent Advances and Future Directions

“…Altogether, these findings suggest that tumor suppression by DAPK3 in GC is associated with autophagy. Recent studies revealed that DAPK3 may act on cisplatin resistance in GC cells by activating the IL-6/STAT3 signaling pathway . In NSCLC, the upregulation of Vir-Like m6A methyltransferase associated (VIRMA) promotes the N 6 -methyladenosine (m6A) modification of DAPK3, and the downregulation of DAPK3 contributes to the progression of NSCLC .…”

“…Recent studies revealed that DAPK3 may act on cisplatin resistance in GC cells by activating the IL-6/STAT3 signaling pathway. 152 In NSCLC, the upregulation of Vir-Like m6A methyltransferase associated (VIRMA) promotes the N 6methyladenosine (m6A) modification of DAPK3, and the downregulation of DAPK3 contributes to the progression of NSCLC. 153 In addition, DAPK3 knockdown inhibits cell proliferation, migration, and invasion through ERK/c-myc signaling in A549 cell lines, suggesting that DAPK3 is a promising target for the treatment of NSCLC 154 (Table 3).…”