Dynamin 3 suppresses growth and induces apoptosis of hepatocellular carcinoma cells by activating inducible nitric oxide synthase production

Dynamin 3 (DNM3) is candidate tumor suppressor against hepatocellular carcinoma (HCC). Downregulation of DNM3 is more frequently identified in HCC tissues than in normal liver tissues. However, the mechanism underlying DNM3-mediated inhibition of HCC remains unclear. The present study demonstrated that DNM3 expression was decreased in human HCC tissues and cell lines. The downregulation of DNM3 promoted cell proliferation by increasing cell cycle-associated proteins, including cyclin D1, cyclin-dependent kinase (CDK) 2 and CDK4. The upregulation of DNM3 induced HCC cell apoptosis and inhibited tumor growth. The present study also revealed that overexpression of DNM3 induced nitric oxide (NO) production and intracellular reactive oxygen species (ROS) accumulation. DNM3 overexpression also increased the protein expression level of inducible nitric oxide synthase (iNOS) in HCC cells and subcutaneous HCC tumor xenografts. The inhibition of iNOS by L-canavanine attenuated the DNM3-induced ROS accumulation and apoptotic cell death. In conclusion, the results indicate that DNM3 overexpression may induce apoptosis and inhibit tumor growth of HCC by activating iNOS production and the subsequent NO-ROS signaling pathways.