Alemtuzumab induction of intracellular signaling and apoptosis in malignant B lymphocytes
Alemtuzumab induction of intracellular signaling and apoptosis in malignant B lymphocytes
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DOI：
10.3109/10428194.2011.623253
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发表时间：
2012-04-01
影响因子：
2.6
通讯作者：
Shankara, Srinivas
中科院分区：
文献类型：
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作者：
Nguyen, Tri-Hung;Havari, Evis;Shankara, Srinivas
研究了CD52与B细胞结合后阿伦图珠单抗诱导的分子变化。Alemtuzumab单独对细胞信号没有可检测到的影响，但抗人Fc抗体使B肿瘤细胞表面的Alemtuzumab产生瞬时的钙离子流动，随后与应激和生存通路有关的几个激酶被磷酸化，并表达包括TNF-α在内的相关蛋白。Alemtuzumab的交联也诱导了肿瘤细胞的封顶和依赖于caspase的细胞凋亡。当使用B-CLL患者的原代细胞时，单独的alemtuzumab能够通过Fc-Gamma RIIb受体与B-CLL细胞上的Alemtuzumab交联来诱导蛋白质磷酸化和细胞凋亡。用抗CD32抗体阻断Fc-γ-RIIb受体可阻止细胞凋亡。综上所述，我们的研究结果表明，阿仑珠单抗可以通过Fc受体的相互作用自然发生在B肿瘤细胞上，并导致特定细胞通路的激活和诱导细胞凋亡。
The molecular changes induced by alemtuzumab following binding of CD52 on B tumor cells were investigated. Alemtuzumab alone had no detectable impact on cell signaling but cross-linking of alemtuzumab on the surface of B tumor lines with anti-human Fc antibodies induced a transient Ca2+ flux followed by phosphorylation of several kinases involved in stress and survival pathways, and expression of associated proteins including TNF-alpha. Cross-linking of alemtuzumab also induced capping and caspase-dependent apoptosis of the tumor lines. When using primary cells from B-CLL patients, alemtuzumab alone was capable of inducing protein phosphorylation and apoptosis through the cross-linking of alemtuzumab by Fc gamma RIIb receptors on B-CLL cells. Apoptosis was prevented by blocking of Fc gamma RIIb receptors with anti-CD32 antibody. Overall, our results indicate that cross-linking of alemtuzumab on B tumor cells can occur naturally through Fc receptor interaction and leads to the activation of specific cellular pathways and induction of apoptosis.