Circadian clock components RORα and Bmal1 mediate the anti-proliferative effect of MLN4924 in osteosarcoma cells
- Oncotarget. 2016 Oct 4;7(40):66087-66099. doi: 10.18632/oncotarget.11807.
- 1. The State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, Hunan 410078, China.
- 2. Xiangya Stomatological Hospital, Central South University, Changsha, Hunan 410078, China.
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.
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Cat. No.Product NameDescriptionTargetResearch Area
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Research Areas: Cancer