Oncotarget

Research Papers:

BM microenvironmental protection of CML cells from imatinib through Stat5/NF-κB signaling and reversal by Wogonin

Xuefen Xu, Xiaobo Zhang, Yicheng Liu, Lin Yang, Shaoliang Huang, Lu Lu, Shuhao Wang, Qinglong Guo _ and Li Zhao

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Oncotarget. 2016; 7:24436-24454. https://doi.org/10.18632/oncotarget.8332

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Abstract

Xuefen Xu1, Xiaobo Zhang1, Yicheng Liu1, Lin Yang1, Shaoliang Huang1, Lu Lu1, Shuhao Wang2, Qinglong Guo1, Li Zhao1

1State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, People’s Republic of China

2Middle School of The City, Mei County, Baoji, Shaanxi 721000, People’s Republic of China

Correspondence to:

Qinglong Guo, e-mail: anticancer_drug@163.com

Li Zhao, e-mail: zhaoli@cpu.edu.cn

Keywords: BM microenvironment, CD34+ subpopulation, Stat5, NF-κB, Wogonin

Received: November 04, 2015     Accepted: March 06, 2016     Published: March 24, 2016

ABSTRACT

Constitutive Stat5 activation enhanced cell survival and resistance to imatinib (IM) in chronic myelogenous leukemia (CML) cells. However, the mechanism of Stat5 activation in mediating resistance to IM in bone marrow (BM) microenvironment has not been evaluated precisely. In this study, we reported HS-5-derived conditioned medium (CM) significantly enhanced IM resistance in K562 and KU812. Interestingly, upregulation of the proportion of CD34+ subpopulation was found in CML cells. Subsequently, the BCR/ABL-independent activation of Stat5 increased P-glycoprotein (P-gp) activity in CM-mediated protection of CML stem cells (LSCs) from IM. Further research revealed Stat5 activation increased the DNA binding activity of NF-κB though binding of p-Stat5 and p-RelA in nucleus. Moreover, highly acetylated RelA was required for Stat5-mediated RelA nuclear binding. The study further confirmed that Wogonin potentiated the inhibitory effects of IM on leukemia development by suppressing Stat5 pathway both in CM model and the K562 xenograft model. In summary, results clearly demonstrated BCR/ABL-independent Stat5 survival pathway could contribute to resistance of CML LSCs to IM in BM microenvironment and suggested that natural durgs effectively inhibiting Stat5 may be an attractive approach to overcome resistance to BCR/ABL kinase inhibitors.


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