Ligand bound beta1 integrins inhibit procaspase-8 for mediating cell adhesion-mediated drug and radiation resistance in human leukemia cells.
Ligand bound beta1 integrins inhibit procaspase-8 for mediating cell adhesion-mediated drug and radiation resistance in human leukemia cells.
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DOI：
10.1371/journal.pone.0000269
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发表时间：
2007-03-07
期刊：
影响因子：
3.7
通讯作者：
Cordes N
中科院分区：
文献类型：
--
作者：
Estrugo D;Fischer A;Hess F;Scherthan H;Belka C;Cordes N
白血病细胞的化疗和放射治疗反应通过整合素介导的与细胞外基质的黏附来改变。为了进一步研究β1整合素诱导放射和化疗耐药的分子机制，我们检测了稳定表达β1整合素的HL6 0人急性早幼粒细胞白血病细胞和缺乏Fas相关死亡结构域蛋白或原天冬氨酸酶8的A3JurkatT淋巴瘤细胞。在X射线、Ara-C或FasL作用下，悬液和贴壁(纤维连接蛋白(FN)、层粘连蛋白、胶原-1；包被浓度为5~100µg/cm2)处理细胞，检测细胞凋亡率、线粒体膜电位(MTP)、半胱氨酸天冬氨酸氨基转移酶(Caspase)活性和蛋白含量。Caspase1整合素的过表达增强了细胞对X射线和Ara-C的敏感性，这一作用可被基质蛋白浓度的增加以及β-3和-8的活性降低和MTP的破坏所抵消。使用刺激性或抑制性抗β1整合素抗体、药理学半胱氨酸氨基转移酶或磷脂酰肌醇3激酶(PI3K)抑制剂、共沉淀实验和siRNA介导的β1整合素沉默提供了进一步的数据，表明FN连接的β1整合素与PI3K/Akt之间存在相互作用，以抑制Proaspase-8的切割。这些数据表明，β1整合素的配体状态对其在经Ara-C、FasL或电离辐射处理的白血病细胞中的抗凋亡作用是至关重要的。抗细胞凋亡作用包括形成β-1整合素/Akt复合体，该复合体以依赖于PI3K的方式发出信号，阻止PI3K-8介导的诱导细胞凋亡。针对β-1整合素和PI3K/Akt信号通路的拮抗剂与常规治疗相结合，可能有效地减少血液系统恶性肿瘤的放疗和耐药肿瘤的数量和治疗失败。
Chemo- and radiotherapeutic responses of leukemia cells are modified by integrin-mediated adhesion to extracellular matrix. To further characterize the molecular mechanisms by which β1 integrins confer radiation and chemoresistance, HL60 human acute promyelocytic leukemia cells stably transfected with β1 integrin and A3 Jurkat T-lymphoma cells deficient for Fas-associated death domain protein or procaspase-8 were examined. Upon exposure to X-rays, Ara-C or FasL, suspension and adhesion (fibronectin (FN), laminin, collagen-1; 5–100 µg/cm2 coating concentration) cultures were processed for measurement of apoptosis, mitochondrial transmembrane potential (MTP), caspase activation, and protein analysis. Overexpression of β1 integrins enhanced the cellular sensitivity to X-rays and Ara-C, which was counteracted by increasing concentrations of matrix proteins in association with reduced caspase-3 and -8 activation and MTP breakdown. Usage of stimulatory or inhibitory anti β1 integrin antibodies, pharmacological caspase or phosphatidylinositol-3 kinase (PI3K) inhibitors, coprecipitation experiments and siRNA-mediated β1 integrin silencing provided further data showing an interaction between FN-ligated β1 integrin and PI3K/Akt for inhibiting procaspase-8 cleavage. The presented data suggest that the ligand status of β1 integrins is critical for their antiapoptotic effect in leukemia cells treated with Ara-C, FasL or ionizing radiation. The antiapoptotic actions involve formation of a β1 integrin/Akt complex, which signals to prevent procaspase-8-mediated induction of apoptosis in a PI3K-dependent manner. Antagonizing agents targeting β1 integrin and PI3K/Akt signaling in conjunction with conventional therapies might effectively reduce radiation- and drug-resistant tumor populations and treatment failure in hematological malignancies.
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影响因子：
4.8
作者：
Gendron, S;Couture, J;Aoudjit, F
通讯作者：
Aoudjit, F
影响因子：
8.8
作者：
Cordes, N;Hansmeier, B;Beinke, C;Meineke, V;van Beuningen, D
通讯作者：
van Beuningen, D
影响因子：
8
作者：
Belka, C;Rudner, J;Schulze-Osthoff, K
通讯作者：
Schulze-Osthoff, K
影响因子：
11.4
作者：
Damiano, JS;Hazlehurst, LA;Dalton, WS
通讯作者：
Dalton, WS
影响因子：
12.4
作者：
Hodkinson, P. S.;Elliott, T.;Sethi, T.
通讯作者：
Sethi, T.