Silencing RRM2 inhibits multiple myeloma by targeting the Wnt/β-catenin signaling pathway

Ribonucleotide reductase M2 (RRM2) is one of the two subunits that comprise ribonucleotide reductase (RR), the enzyme that catalyzes the conversion of ribonucleotide 5'-diphosphates into 2'-deoxyribonucleotides, which are required for DNA synthesis. RRM2 is a stress response factor important for the development of several tumors. However, its role in multiple myeloma (MM) remains to be fully elucidated. The present study aimed to investigate the role of RRM2 in MM. The expression of RRM2 in patients with MM was analyzed using the Oncomine database. The results demonstrated that RRM2 expression was higher in MM compared with healthy subjects. Reverse transcription-quantitative polymerase chain reaction and western blot results revealed that RRM2 expression was decreased following transfection with a small interfering RNA targeting RRM2 into NCI-H929 cells. RR activity and Cell Counting Kit-8 assays demonstrated that RRM2 silencing reduced RR activity and inhibited cell proliferation. Annexin V-propidium iodide staining indicated that the percentage of apoptotic NCI-H929 cells was increased following RRM2 silencing compared with that in the control group. Increased phosphorylation of H2AX indicated that RRM2 silencing may activate the DNA-damage response pathway in NCI-H929 cells. Western blot analysis revealed that protein levels of the apoptosis-associated factor Bcl-2 were reduced, whereas Bax, cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase 1 were upregulated following RRM2 silencing compared with the control group. In addition, the results demonstrated that RRM2 silencing may inhibit target gene expression in the Wnt/beta-catenin signaling pathway by increasing the phosphorylation of glucose synthase kinase 3 beta. These findings indicated that RRM2 may be involved in the proliferation and apoptosis of MM cells via the Wnt/beta-catenin signaling pathway, suggesting that RRM2 may represent a novel therapeutic target for MM.