MLN4924 suppresses neddylation and induces cell cycle arrest, senescence, and apoptosis in human osteosarcoma

// Yi Zhang 1, 2, * , Cheng-Cheng Shi 2, 3, * , Hua-Peng Zhang 4, 5 , Gong-Quan Li 4, 5 , Shan-Shan Li 6 1 Department of Orthopaedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China 2 The Hormel Institute, University of Minnesota, Austin, MN, USA 3 Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China 4 Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China 5 Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China 6 Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China * These authors have contributed equally to this work Correspondence to: Yi Zhang, email: zhangyimed@163.com Keywords: osteosarcoma, neddylation, MLN4924 Received: December 20, 2015      Accepted: March 31, 2016      Published: May 19, 2016 ABSTRACT Neddylation is a post-translational protein modification process associated with carcinogenesis and cancer development. MLN4924, a pharmaceutical neddylation inhibitor, induces potent anti-cancer effects in multiple types of cancers. In this study, we investigated the effects of MLN4924 on human osteosarcoma (OS). Levels of both NEDD8 activating enzyme E1 (NAE1) and ubiquitin-conjugating enzyme E2M (Ube2M), two critical components of the neddylation pathway, were much higher in OS tissues and cells than in normal osseous tissues and cells. MLN4924 treatment led to DNA damage, reduced cell viability, senescence and apoptosis in OS cells. Moreover, MLN4924 inhibited OS xenograft tumor growth in mice. Mechanistically, MLN4924 blocked the neddylation of cullins and induced accumulation of several tumor-suppressive substrates of Cullin-RING E3 ubiquitin ligases (CRLs), including CDT1, Wee1, p21, p27, Noxa, and p16. These results suggest clinical studies investigating the utility of MLN4924 for the treatment of OS are warranted.