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

Shuju Zhang1, Jiaming Zhang1, Zhiyuan Deng2

  • 1The State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, Hunan 410078, China.

Oncotarget
|September 8, 2016
PubMed

Insights

The anticancer drug MLN4924 inhibits osteosarcoma cell growth by inducing cell cycle arrest and apoptosis. This effect is mediated by the circadian clock genes retinoid orphan nuclear receptor alpha (RORα) and Bmal1.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • MLN4924 is a Nedd8-activating enzyme (NAE) inhibitor with known anticancer properties.
  • Osteosarcoma is a primary bone cancer with limited treatment options.

Purpose of the Study:

  • To investigate the mechanism by which MLN4924 suppresses osteosarcoma cell proliferation.
  • To identify key molecular targets involved in MLN4924's anti-cancer effects in osteosarcoma.

Main Methods:

  • MLN4924 treatment of U2OS osteosarcoma cells.
  • Assessment of cell cycle progression, apoptosis, and protein ubiquitination.
  • RNA interference (siRNA) to deplete RORα and Bmal1 expression.
  • Quantitative analysis of p21 and Bmal1 gene expression.

Main Results:

  • MLN4924 induced G2/M cell cycle arrest and apoptosis in osteosarcoma cells.
  • MLN4924 stabilized RORα by reducing its ubiquitination, and RORα depletion attenuated MLN4924's anti-proliferative effect.
  • MLN4924 upregulated RORα targets p21 and Bmal1, with Bmal1 playing a crucial role in mediating the anti-proliferative effect.

Conclusions:

  • MLN4924 is a potential therapeutic agent for osteosarcoma.
  • MLN4924-induced tumor growth inhibition involves the circadian clock components RORα and Bmal1.
Keywords:
Bmal1MLN4924RORαneddylationosteosarcoma

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