Biologic sequelae of c-Jun NH2-terminal kinase (JNK) activation in multiple myeloma cell lines
Biologic sequelae of c-Jun NH2-terminal kinase (JNK) activation in multiple myeloma cell lines
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DOI：
10.1038/sj.onc.1206919
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发表时间：
2003-11-27
期刊：
影响因子：
8
通讯作者：
Anderson, K
中科院分区：
文献类型：
--
作者：
Hideshima, T;Hayashi, T;Anderson, K
虽然c-Jun NH 2-末端激酶（JNK）被激活的治疗药物的治疗，抑制JNK的组成性激活的生物学后遗症尚未得到澄清。在这项研究中，我们研究了JNK抑制在多发性骨髓瘤（MM）细胞系中的生物学效应。JNK特异性抑制剂SP 600125分别通过诱导U266和MM. 1 S多发性骨髓瘤细胞系中的G1或G2/M停滞来诱导生长抑制。外源性IL-6和胰岛素样生长因子-1（IGF-1）均不能克服SP 600125诱导的MM. 1 S细胞生长抑制，IL-6可增强SP 600125诱导的MM. 1 S细胞G2/M期。生长停滞的诱导是通过上调p27（Kip 1）介导的，而不改变p53和JNK蛋白表达。重要的是，SP 600125抑制粘附于骨髓基质细胞（BMSC）的MM细胞的生长。SP 600125以剂量依赖性方式诱导NF-κ B活化，与IkappaB激酶α（IKK α）磷酸化和IkappaB α降解相关。相反，SP 600125不影响STAT 3、Akt和/或ERK的磷酸化。IKK特异性抑制剂PS-1145抑制SP 600125诱导的NF-κ B活化并阻断SP 600125对细胞凋亡的保护作用。因此，我们的数据首次表明，抑制JNK活性诱导生长停滞和激活MM细胞中的NF-κ B。
Although c-Jun NH2-terminal kinase (JNK) is activated by treatment with therapeutic agents, the biologic sequelae of inhibiting constitutive activation of JNK has not yet been clarified. In this study, we examine the biologic effect of JNK inhibition in multiple myeloma (MM) cell lines. JNK-specific inhibitor SP600125 induces growth inhibition via induction of G1 or G2/M arrest in U266 and MM.1S multiple myeloma cell lines, respectively. Neither exogenous IL-6 nor insulin-like growth factor-1 (IGF-1) overcome SP600125-induced growth inhibition, and IL-6 enhances SP600125-induced G2/M phase in MM.1S cells. Induction of growth arrest is mediated by upregulation of p27(Kip1), without alteration of p53 and JNK protein expression. Importantly, SP600125 inhibits growth of MM cells adherent to bone marrow stromal cells (BMSCs). SP600125 induces NF-kappaB activation in a dose-dependent fashion, associated with phosphorylation of IkappaB kinase alpha (IKKalpha) and degradation of IkappaBalpha. In contrast, SP600125 does not affect phosphorylation of STAT3, Akt, and/or ERK. IKK-specific inhibitor PS-1145 inhibits SP600125-induced NF-kappaB activation and blocks the protective effect of SP600125 against apoptosis. Our data therefore demonstrate for the first time that inhibiting JNK activity induces growth arrest and activates NF-kappaB in MM cells.