Hess F, Estrugo D, Fischer A, Belka C, Cordes N
Bundeswehr Institute of Radiobiology, Munich, Germany.
Oncogene. 2007 Mar 1;26(10):1372-84. doi: 10.1038/sj.onc.1209947. Epub 2006 Aug 28.
Integrin-mediated adhesion of leukemia cells to extracellular matrix proteins reduces apoptosis following radiation-induced genotoxic injury. To evaluate the role of integrin-linked kinase (ILK) in this process, HL60 human acute promyelocytic leukemia cells were stably transfected with ILK wild-type or kinase-hyperactive overexpression vectors. Suspension or fibronectin (FN) adhesion cultures were irradiated with X-rays and processed for measurement of apoptosis, mitochondrial transmembrane potential and caspase activation. Adhesion to FN pronouncedly reduced radiation-induced apoptosis of HL60 cells and vector controls. Intriguingly, overexpressed ILK enhanced apoptosis after irradiation by combined activation of caspase-3 through caspase-8 and -9 in irradiated FN cultures. Irradiation of ILK suspension cultures lacked caspase-8 activation, but showed serial cleavage of caspase-9, -3 and poly (ADP-ribose) polymerase. These findings further characterize the cell death-promoting function of ILK in DNA-damaged cells. Moreover, ILK might represent a potential therapeutic target for innovative chemo- and radiooncological approaches in hematological malignancies.
整合素介导的白血病细胞与细胞外基质蛋白的黏附可减少辐射诱导的基因毒性损伤后的细胞凋亡。为了评估整合素连接激酶（ILK）在此过程中的作用，用ILK野生型或激酶高活性过表达载体稳定转染HL60人急性早幼粒细胞白血病细胞。对悬浮培养或纤连蛋白（FN）黏附培养的细胞进行X射线照射，并进行细胞凋亡、线粒体跨膜电位和半胱天冬酶激活的检测。黏附于FN可显著降低HL60细胞和载体对照的辐射诱导凋亡。有趣的是，在照射后的FN培养物中，过表达的ILK通过半胱天冬酶-8和-9联合激活半胱天冬酶-3，从而增强照射后的细胞凋亡。ILK悬浮培养物经照射后缺乏半胱天冬酶-8激活，但显示半胱天冬酶-9、-3和聚（ADP-核糖）聚合酶的系列裂解。这些发现进一步阐明了ILK在DNA损伤细胞中的促细胞死亡功能。此外，ILK可能是血液系统恶性肿瘤创新化疗和放疗方法的潜在治疗靶点。
