Oncotarget

Research Papers:

Toxicity of JQ1 in neuronal derivatives of human umbilical cord mesenchymal stem cells

Shreeya Bakshi, Christina McKee, Keegan Walker, Christina Brown and G. Rasul Chaudhry _

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Oncotarget. 2018; 9:33853-33864. https://doi.org/10.18632/oncotarget.26127

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Abstract

Shreeya Bakshi1,2, Christina McKee1,2, Keegan Walker1,2, Christina Brown1,2 and G. Rasul Chaudhry1,2

1Department of Biological Sciences, Oakland University, Rochester, MI 48309, USA

2OU-WB Institute for Stem Cell and Regenerative Medicine, Oakland University, Rochester, MI 48309, USA

Correspondence to:

G. Rasul Chaudhry, email: chaudhry@oakland.edu

Keywords: JQ1; BET inhibitor; mesenchymal stem cells; apoptosis; neuronal differentiation

Received: June 11, 2018     Accepted: September 01, 2018     Published: September 18, 2018

ABSTRACT

Bromodomain and extra-terminal domain (BET) proteins regulate the transcription of many genes including c-MYC, a proto-oncogene, which is upregulated in many types of cancers. The thienodiazepine class of BET inhibitors, such as JQ1, inhibits growth of cancer cells and triggers apoptosis. However, the effects of BET inhibitors on normal cells and mesenchymal stem cells (MSCs), which are important in routine maintenance or regeneration of damaged cells and tissues, are poorly investigated. Previously, we have shown that JQ1 causes human umbilical cord MSCs to undergo cell cycle arrest and neural differentiation. In this study, we determined that JQ1 is more deleterious to neuronal derivatives (NDs) than adipogenic, chondrogenic or osteogenic derivatives of MSCs. NDs treated with JQ1 showed a significant decrease in cell proliferation, viability, and neuronal markers. JQ1 caused cell death through the intrinsic apoptotic pathway in NDs as determined by activation of Caspase 9 and increased expression of Cytochrome C. A comparative analysis showed differential action of JQ1 on MSCs and NDs. The results showed selective neuronal toxicity of JQ1 in NDs but not in the undifferentiated MSCs. These findings suggest a more careful examination of the selection and use of BET inhibitors as therapeutic agents, as they may cause unwanted damage to non-target cells and tissues.


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