Circadian clock components RORα and Bmal1 mediate the anti-proliferative effect of MLN4924 in osteosarcoma cells

• Published in: Oncotarget Vol. 7; no. 40; pp. 66087 - 66099
• Main Authors: Zhang, Shuju, Zhang, Jiaming, Deng, Zhiyuan, Liu, Huadie, Mao, Wei, Jiang, Fang, Xia, Zanxian, Li, Jia-Da
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 04.10.2016
• Subjects: Animals; Apoptosis - drug effects; ARNTL Transcription Factors - metabolism; Biomarkers, Tumor - metabolism; Bone Neoplasms - drug therapy; Bone Neoplasms - metabolism; Bone Neoplasms - pathology; Cell Proliferation - drug effects; Circadian Clocks; Cyclopentanes - pharmacology; Enzyme Inhibitors - pharmacology; Humans; Mice; Mice, Nude; Nuclear Receptor Subfamily 1, Group F, Member 1 - metabolism; Osteosarcoma - drug therapy; Osteosarcoma - metabolism; Osteosarcoma - pathology; Pyrimidines - pharmacology; Research Paper; Tumor Cells, Cultured; Xenograft Model Antitumor Assays; neddylation; RORα; MLN4924; Bmal1; osteosarcoma
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.11807

The anticancer small molecule MLN4924, a Nedd8-activating enzyme (NAE) inhibitor, triggers cell-cycle arrest, apoptosis, and senescence in cancer cells. In this study, we demonstrate that MLN4924 suppresses osteosarcoma cell proliferation by inducing G2/M cell cycle arrest and apoptosis. Our results indicate that MLN4924 stabilizes the retinoid orphan nuclear receptor alpha (RORα) by decreasing its ubiquitination. RNA interference of RORα attenuates the anti-proliferative effect of MLN4924 in U2OS osteosarcoma cells. MLN4924 up-regulates the expression of p21 and Bmal1, two transcriptional targets of RORα. However, p21 plays a minimal role in the anti-proliferative effect of MLN4924 in U2OS osteosarcoma cells. In contrast, Bmal1 suppression by siRNA attenuates the anti-proliferative effect of MLN4924 in U2OS osteosarcoma cells, indicating that the MLN4924-mediated cell growth inhibition is mediated by Bmal1. These results show MLN4924 to be a promising therapeutic agent for the treatment of osteosarcoma and suggest that MLN4924-induced tumor growth inhibition is mediated by the circadian clock components RORα and Bmal1.