Midkine promotes tumor growth and attenuates the effect of cisplatin in small cell lung cancer

Purpose Small cell lung cancer (SCLC) is a highly aggressive disease with poor survival. Nevertheless, the addition of an anti-programmed death ligand 1 antibody to platinum combination chemotherapy can improve its prognosis. However, only a few patients achieve a long-term response; thus, establishing new therapies for SCLC is crucial. Midkine (MDK) is a heparin-binding growth factor that plays a role in various biological processes such as cell proliferation and chemotherapy resistance in diverse cancers. MDK has garnered attention as a therapeutic and diagnostic target for several cancers; however, studies evaluating its expression and function in SCLC are scarce. Methods The MDK expression was analyzed in vitro and in vivo by ELISA, immunohistochemistry, western blotting. The effect of MDK on cell proliferation and the effect of cisplatin was evaluated by MTT assay. Results MDK was expressed pathologically in human SCLC tumor tissues but not in normal lung tissues. Human serum MDK concentration in patients with SCLC reflected the SCLC tumor burden and was correlated to the response to treatment. Moreover, MDK induced cell proliferation and attenuated the effect of cisplatin in SCLC cell lines. The combination of an MDK inhibitor and cisplatin exerted synergistic antitumor effects both in vitro and in vivo. Additionally, MDK positively regulated the AKT pathway. Conclusion The present results indicate that MDK contributes to cell proliferation and chemotherapy resistance by activating the AKT pathway in SCLC. Therefore, MDK may be a potential therapeutic and diagnostic target for SCLC.