Acylglycerol kinase promotes ovarian cancer progression and regulates mitochondria function by interacting with ribosomal protein L39

Abstract

BackgroundEpithelial ovarian cancer (EOC) is the leading cause of deaths among patients with gynecologic malignancies. In recent years, cancer stem cells (CSCs) have attracted great attention, which have been regarded as new biomarkers and targets in cancer diagnoses as well as therapies. However, therapeutic failure caused by chemotherapy resistance in late-stage EOC occurs frequently. The 5-year survival rate of patients with EOC remains at about 30%.MethodsIn this study, the expression of acylglycerol kinase (AGK) was analyzed among patients with EOC. The effect of AGK on EOC cell proliferation and tumorigenicity was studied using Western blotting, flow cytometry, EdU assay and in vivo xenotransplantation assays. Furthermore, AGK induced CSC-like properties and was resistant to cisplatin chemotherapy in the EOC cells, which were investigated through sphere formation assays and the in vivo model of chemoresistance. Finally, the relationship between AGK and RPL39 (Ribosomal protein L39) in mitochondria as well as their effect on the mitochondrial function was analyzed through methods including transmission electron microscopy, microarray, biotin identification and immunoprecipitation.ResultsAGK showed a markedly upregulated expression in EOC, which was significantly associated with the poor survival of patients with EOC, the expression of AGK-promoted EOC cell proliferation and tumorigenicity. AGK also induced CSC-like properties in the EOC cells and was resistant to cisplatin chemotherapy. Furthermore, the results indicated that AGK not only maintained mitochondrial cristae morphogenesis, but also increased the production of reactive oxygen species and Δψm of EOC cells in a kinase-independent manner. Finally, our results revealed that AGK played its biological function by directly interacting with RPL39.ConclusionsWe demonstrated that AGK was a novel CSC biomarker for EOC, which the stemness of EOC was promoted and chemotherapy resistance was developed through physical as well as functional interaction with RPL39.