MJ-29 inhibits tubulin polymerization, induces mitotic arrest, and triggers apoptosis via cyclin-dependent kinase 1-mediated Bcl-2 phosphorylation in human leukemia U937 cells

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Title:	MJ-29 inhibits tubulin polymerization, induces mitotic arrest, and triggers apoptosis via cyclin-dependent kinase 1-mediated Bcl-2 phosphorylation in human leukemia U937 cells
Authors:	楊家欣;Yang, Jai-Sing;侯曼貞;Hour, Mann-Jen;黃雯雯;Huang, Wen-Wen;Lin, Kuei-Li;Kuo, Sheng-Chu;鍾景光;Chung, Jing-Gung
Contributors:	生物科技學系
Date:	2010-08
Issue Date:	2012-11-23 17:13:35 (UTC+8)
Abstract:	We investigated the signaling pathways associated with microtubule interaction and apoptosis in U937 cells in vitro and in the U937 xenograft model in vivo by using 6-pyrrolidinyl-2-(2-hydroxyphenyl)-4-quinazolinone (MJ-29). MJ-29 induced growth inhibition and cell death of leukemia cell lines (U937, HL-60, K562, and KG-1) in a dose- and time-dependent manner but did not obviously impair the viability of normal cells (peripheral blood mononuclear cells and human umbilical vein endothelial cells). MJ-29 interacted with alpha- and beta-tubulin, inhibited tubulin polymerization both in vitro and in vivo, and disrupted microtubule organization. MJ-29 caused mitotic arrest by activating cyclin-dependent kinase 1 (CDK1)/cyclin B complex activity. MJ-29-induced growth inhibition and activation of CDK1 activity were significantly attenuated by roscovitine (CDK inhibitor) and CDK1 small interfering RNA (siRNA). Furthermore, MJ-29-induced Bcl-2 phosphorylation was also significantly attenuated by CDK1 siRNA. MJ-29 caused an increase in the protein levels of cytosolic cytochrome c, apoptotic protease-activating factor-1, procaspase-9, and apoptosis-inducing factor. MJ-29-promoted activation of caspase-9 and caspase-3 during apoptosis was significantly attenuated by caspase-9 and caspase-3 inhibitors. It is noteworthy that in BALB/c(nu/nu) mice bearing U937 xenograft tumors MJ-29 inhibited tumor growth in vivo. The terminal deoxynucleotidyl transferase-mediated d-UTP nick end-labeling-positive apoptotic cells of tumor sections significantly increased in MJ-29-treated mice compared with the control group. In conclusion, our results suggest that MJ-29 induces mitotic arrest and apoptosis in U937 cells via CDK1-mediated Bcl-2 phosphorylation and inhibits the in vivo tumor growth of U937 xenograft mice.
Relation:	JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Appears in Collections:	[生物科技學系] 期刊論文

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