The Membrane-Proximal KXGFFKR Motif of α-Integrin Mediates Chemoresistance
The Membrane-Proximal KXGFFKR Motif of α-Integrin Mediates Chemoresistance
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DOI：
10.1128/mcb.00580-13
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发表时间：
2013-11-01
影响因子：
5.3
通讯作者：
Lim, Chinten James
中科院分区：
文献类型：
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作者：
Liu, Chi-Chao;Leclair, Pascal;Lim, Chinten James
细胞粘附介导的耐药性导致血液恶性肿瘤中的微小残留病和复发。在这里，我们发现 Jurkat T 急性淋巴细胞白血病细胞与 α 4 δ 1-整联蛋白或 α 5 β 1-整联蛋白结合的底物的粘附促进了对阿霉素诱导的细胞凋亡的化学抗性。 α 4 δ（一种以 KXGFFKR 作为细胞质基序的截短的 α 4 整合素）在 α 4 缺陷细胞中的重建表达，以不依赖于 α 4 介导的粘附的方式促进对阿霉素的化疗耐药性。粘附独立的化学抗性不需要β1-整合素作为异二聚体对，因为Tac δ（一种与近膜KXGFFKR融合的单体非整合素跨膜蛋白）的表达足以重现该现象。对于表达 alpha 4 delta 和 Tac delta 的细胞，绕过了刺激 Akt 磷酸化和激活时整合素介导的粘附的要求。表达α4δ和Tacδ的细胞表现出大量的细胞外Ca2+流入，并且用维拉帕米抑制Ca2+通道减弱了粘附非依赖性化疗耐药性。 Tac delta 细胞还表现出更高的药物流出率。 α 4 δ 和 Tac δ 与 Ca2+ 结合蛋白钙网蛋白相互作用，其方式依赖于 KXGFFKR 基序。与非贴壁细胞相比，粘附介导的α4-整合素的结合促进了钙网蛋白-α4关联的增加和更多的细胞外Ca2+流入。 α-整合素 KXGFFKR 基序参与 T 细胞中化学耐药性的粘附介导控制。
Cell adhesion-mediated drug resistance contributes to minimal residual disease and relapse in hematological malignancies. Here, we show that adhesion of Jurkat T-acute lymphoblastic leukemia cells to substrates engaging alpha 4 delta 1-integrin or alpha 5 beta 1-integrin promotes chemoresistance to doxorubicin-induced apoptosis. Reconstituted expression of alpha 4 delta, a truncated alpha 4-integrin with KXGFFKR as the cytoplasmic motif, in alpha 4-deficient cells promoted chemoresistance to doxorubicin in a manner independent of alpha 4-mediated adhesion. The adhesion-independent chemoresistance did not require beta 1-integrin as the heterodimeric pair, since expression of Tac delta, a monomeric nonintegrin transmembrane protein fused to the juxtamembrane KXGFFKR, was sufficient to reproduce the phenomenon. The requirement for integrin-mediated adhesion in stimulation of Akt phosphorylation and activation was bypassed for cells expressing alpha 4 delta and Tac delta. Cells expressing alpha 4 delta and Tac delta exhibited a high influx of extracellular Ca2+, and inhibition of Ca2+ channels with verapamil attenuated the adhesion-independent chemoresistance. Tac delta cells also exhibited greater rates of drug efflux. alpha 4 delta and Tac delta interacted with the Ca2+-binding protein calreticulin, in a manner dependent on the KXGFFKR motif. Adhesion-mediated engagement of alpha 4-integrins promoted an increased calreticulin-alpha 4 association and greater influx of extracellular Ca2+ than in nonadherent cells. The alpha-integrin KXGFFKR motif is involved in adhesion-mediated control of chemoresistance in T cells.