BM microenvironmental protection of CML cells from imatinib through Stat5/NF-κB signaling and reversal by Wogonin.
BM microenvironmental protection of CML cells from imatinib through Stat5/NF-κB signaling and reversal by Wogonin.
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伊马替尼通过 Stat5/NF-kappa B 信号传导和汉黄芩素逆转对 CML 细胞的 BM 微环境保护
DOI：
10.18632/oncotarget.8332
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发表时间：
2016-04-26
期刊：
影响因子：
--
通讯作者：
Zhao L
中科院分区：
文献类型：
--
作者：
Xu X;Zhang X;Liu Y;Yang L;Huang S;Lu L;Wang S;Guo Q;Zhao L
结构型Stat5激活增强了慢性粒细胞白血病(CML)细胞的存活率和对伊马替尼(IM)的耐药性。然而，在骨髓微环境中，Stat5激活在介导IM耐药中的作用机制尚未得到准确的评价。在这项研究中，我们报道了HS-5衍生的条件培养液(CM)显著增强了K562和KU812对IM的抵抗。有趣的是，在CML细胞中发现CD34+亚群比例上调。随后，非bcr/abl依赖的Stat5激活增加了CM介导的CML干细胞(LSCs)抗IM的P-糖蛋白(P-gp)活性。进一步的研究发现，STAT5的激活通过与核内的p-STAT5和p-κ结合而增加了NF-RELA的DNA结合活性。此外，STAT5介导的relA核结合需要高度乙酰化的relA。本研究进一步证实汉黄素通过抑制CM模型和K562移植瘤模型中的Stat5通路，增强了IM对白血病发展的抑制作用。综上所述，这些结果清楚地表明，在骨髓微环境中，非bcr/abl非依赖的Stat5生存通路可能参与了CML LSCs对IM的耐药性，并提示有效抑制Stat5的天然药物可能是克服对bcr/abl激酶抑制剂耐药性的一种有吸引力的方法。
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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Fe3O4和汉黄芩素磁性纳米粒子对逆转K562/A02细胞系多药耐药性的影响
影响因子：
8
作者：
Cheng J;Cheng L;Chen B;Xia G;Gao C;Song H;Bao W;Guo Q;Zhang H;Wang X
通讯作者：
Wang X
影响因子：
158.5
作者：
Druker, Brian J.;Guilhot, Francois;Larson, Richard A.
通讯作者：
Larson, Richard A.
DOI：
10.1073/pnas.95.14.8081
发表时间：
1998-07-07
影响因子：
11.1
作者：
Besançon, F;Atfi, A;Bourgeade, MF
通讯作者：
Bourgeade, MF
影响因子：
158.5
作者：
Kantarjian, Hagop;Giles, Francis;Ottmann, Oliver G.
通讯作者：
Ottmann, Oliver G.
影响因子：
4.4
作者：
Mora, AL;Youn, J;Boothby, M
通讯作者：
Boothby, M