Nuclear factor-κB and STAT3 are constitutively active in CD138+ cells derived from multiple myeloma patients, and suppression of these transcription factors leads to apoptosis
Nuclear factor-κB and STAT3 are constitutively active in CD138+ cells derived from multiple myeloma patients, and suppression of these transcription factors leads to apoptosis
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DOI：
10.1182/blood-2003-06-2151
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发表时间：
2004-04-15
期刊：
影响因子：
20.3
通讯作者：
Aggarwal, BB
中科院分区：
文献类型：
--
作者：
Bharti, AC;Shishodia, S;Aggarwal, BB
化疗耐药是多发性骨髓瘤（MM）患者治疗中的一个主要问题。由于核转录因子核因子- kappab （NF-kappaB）和转录信号换能器和激活因子3 （STAT3）在化疗耐药、细胞存活和增殖中的核心作用，我们研究了来自患者的MM细胞是否表达活化的NF-kappaB和STAT3，以及它们的抑制是否诱导凋亡。我们检测了22例MM患者骨髓中的CD138（+）细胞，并通过免疫细胞化学检查了NF-kappaB和STAT3的活化形式。我们发现，所有患者的MM细胞都表达NF-kappaB和STAT3的活化形式，但程度不同（NF-kappaB：低，22例中3例；中等，22例中5例；或高，22例中14例；STAT3：无，22例中1例；低，22例中3例；中等，22例中5例；或高，22例中14例）。在某些情况下，NF-kappaB的组成激活也被电泳迁移率凝胶转移试验独立证实。与MM患者相比，健康个体的细胞中缺乏活化形式的NF-kappaB和STAT3。姜黄素（二乙基甲烷）体外处理抑制MM细胞中NF-kappaB和STAT3的激活，导致骨髓基质细胞粘附减少，细胞因子分泌减少，细胞活力降低。与姜黄素相比，地塞米松在抑制骨髓瘤细胞NF-kappaB活化和诱导细胞凋亡方面效果较差。总的来说，我们的研究结果表明，来自MM患者的新鲜细胞表达组成型活性NF-kappaB和STAT3，抑制这些转录因子会抑制细胞的存活。(C) 2004年由美国血液病学会出版。
Chemoresistance is a major problem in the treatment of patients with multiple myeloma (MM). Because of the central role of the nuclear transcription factors nuclear factor-kappaB (NF-kappaB) and signal transducer and activator of transcription 3 (STAT3) in chemoresistance, cell survival, and proliferation, we investigated whether MM cells derived from patients express activated NF-kappaB and STAT3 and if their suppression induces apoptosis. We assayed CD138(+) cells from the bone marrow of 22 MM patients and checked for the activated forms of NF-kappaB and STAT3 by immunocytochemistry. We found that MM cells from all the patients expressed the activated forms of NF-kappaB and STAT3 but to a variable degree (NF-kappaB: low, 3 of 22; moderate, 5 of 22; or high, 14 of 22; STAT3: none, 1 of 22; low, 3 of 22; moderate, 5 of 22; or high, 14 of 22). Constitutive activation of NF-kappaB was in some cases also independently confirmed by electrophoretic mobility gel shift assay. In contrast to MM patients, activated forms of NF-kappaB and STAT3 were absent in cells from healthy individuals. Suppression of NF-kappaB and STAT3 activation in MM cells by ex vivo treatment with curcumin (diferuloylmethane) resulted in a decrease in adhesion to bone marrow stromal cells, cytokine secretion, and in the viability of cells. When compared with curcumin, dexamethasone was less effective in suppression of NF-kappaB activation and induction of apoptosis in myeloma cells. Overall, our results indicate that fresh cells from MM patients express constitutively active NF-kappaB and STAT3, and suppression of these transcription factors inhibits the survival of the cells. (C) 2004 by The American Society of Hematology.