Abstract
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.
Highlights
Osteosarcoma is the most common primary malignant bone tumor in children and adolescents
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
The most well characterized substrates of Nedd8 are the cullin proteins, the scaffold components of Cullin-Ring E3-ubiquitin Ligases (CRLs) that are responsible for ubiquitination of ~20% of cellular proteins degraded through the ubiquitin-proteasome system [3]
Summary
Osteosarcoma is the most common primary malignant bone tumor in children and adolescents. In the past four decades, osteosarcoma has been treated with neoadjuvant chemotherapy followed by surgical removal of the primary tumor, often followed by additional adjuvant chemotherapy after the surgery. MLN4924 (pevonedistat), a selective Nedd activating enzyme (NAE) inhibitor, is an anti-cancer drug currently in clinical trials [4, 5]. Treatment with MLN4924 can suppress the progression of a variety of tumors [6,7,8,9,10,11,12,13,14]. Various CRLs substrates have been proposed to mediate the anti-cancer effects of MLN4924 [5, 15,16,17]
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