Integrin-linked kinase interacts with caspase-9 and -8 in an adhesion-dependent manner for promoting radiation-induced apoptosis in human leukemia cells

Abstract

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 (ADPribose) polymerase. These findings further characterize the cell death-promoting function of ILK in DNAdamaged cells. Moreover, ILK might represent a potential therapeutic target for innovative chemo-and radiooncological approaches in hematological malignancies.

JNK1 determines the oncogenic or tumor-suppressive activity of the integrin-linked kinase in human rhabdomyosarcoma

“…Intriguingly, expression of PAX3-FKHR in these cells rescued the dampened growth induced by ILK overexpression, similar to ERMS cells. These results are strongly indicative of a conserved role for ILK as a tumor suppressor in certain mesenchymal lineage cells and are consistent with similar data demonstrating ILK-induced differentiation of rat myoblasts (12) and cooperative interactions between ionizing radiation and ILK in the stimulation of apoptosis of HL60 acute promyelocytic leukemia and Jurkat T cells (16).…”

“…Furthermore, a dominant-negative ILK mutant, E359K, blocks cell cycle exit and differentiation of L6 rat myoblasts (12). Similarly, ILK expression correlates in many tumor and normal tissues with areas of increased differentiation (13) and can cooperate with ionizing radiation to induce apoptosis in some cancer cells (14)(15)(16). Finally, overexpression of wild-type, but not mutant, ILK could limit tumor formation in MDA-MB-435 xenografts (17), although the mechanism for this finding was not reported.…”

Identification of Subtilase Cytotoxin (SubAB) Receptors Whose Signaling, in Association with SubAB-Induced BiP Cleavage, Is Responsible for Apoptosis in HeLa Cells

“…Interaction between ligands and ITGs affects a large variety of signal transduction events that serve to modulate many aspects of cell behavior, including proliferation, survival/apoptosis, shape, polarity, motility, gene expression, and differentiation (34). ITG-mediated cell attachment promotes survival signaling in many types of normal cells, even in the presence of various apoptotic stimuli (2-4, 16, 19, 39, 56, 79), while ITGs have been shown to enhance signal transduction pathways leading to cell death (9,29,38,44,52,66). These reports indicate that ITG-mediated signaling regulates both cell survival and cell death, but the detailed mechanisms of integrinmediated apoptosis are poorly understood.…”

Oncogenic ILK, tumor suppression and all that JNK

“…24 Similar evidence has been reported in a limited subset of primary breast tumors, 51 and stable overexpression of ILK in low-expressing MDA-MB-435 breast carcinoma cells suppresses invasion through vitronectin, proliferation in vitro and tumor formation and lung metastases when xenografted into the mammary fat pad of NCr nu/nu mice, in vivo. 51 Furthermore, ILK and the hyperactive kinase mutant ILK-S343D synergize with ionizing radiation to induce apoptosis in A549, FaDu, HL60 and Jurkat T cells, [52][53][54] indicating a potential pro-apoptotic function for ILK in response to radiation, in addition to its antiproliferative function in xenograft studies. 51 In primary tumors, evidence suggests that ILK may be either a tumor suppressor, oncogene or, in fact, exhibit neither function.…”