title: Targeting integrin-linked kinase inhibits Akt signaling pathways and decreases tumor progression of human glioblastoma.
abstract: The phosphatidylinositol 3-kinase pathway is an important regulator of a wide spectrum of tumor-related biological processes, including cell proliferation, survival, and motility, as well as neovascularization. Protein kinase B/Akt is activated in a complex manner through the phosphorylation of protein kinase B/Akt on Thr308 and Ser473. Although protein-dependent kinase-1 has been shown to phosphorylate Akt at Thr308, it is not clear whether there is a distinct kinase that exclusively phosphorylates Akt at Ser473. A possible candidate is integrin-linked kinase (ILK), which has been shown to phosphorylate Akt at Ser473 in vitro. ILK is a multidomain focal adhesion protein that is believed to be involved in signal transmission from integrin and growth factor receptors. Further, ILK is implicated in the regulation of anchorage-dependent cell growth/survival, cell cycle progression, invasion and migration, and tumor angiogenesis. In this study, we tested the hypothesis that ILK inhibition would inhibit these processes in gliomas in which it is constitutively expressed. We found that a newly developed small-molecule compound (QLT0267) effectively inhibited signaling through the ILK/Akt cascade in glioma cells by blocking the phosphorylation of Akt and downstream targets, including mammalian target of rapamycin and glycogen synthase kinase-3beta. Treatment of glioma cells with 12.5 micromol/L QLT0267 inhibited cell growth by 50% at 48 hours. An anchorage-dependent cell growth assay confirmed the cell growth-inhibitory effect of QLT0267. Further, the decrease in cell growth was associated with a dramatic accumulation of cells in the G2-M phase of the cell cycle. Although the cell growth-inhibitory effects of the ILK inhibitor were achieved only at a high concentration, the QLT0267 was able to reduce cellular invasion and angiogenesis at much lower concentrations as shown by in vitro invasion assays and vascular endothelial growth factor secretion. Thus, blocking the ILK/Akt pathway is a potential strategy for molecular targeted therapy for gliomas.
authors.affiliation: Brain Tumor Center, Department of Neuro-Oncology, The University of Texas M.D. Anderson Cancer Center, Unit 100, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
authors.forename: Dimpy
authors.initials: D
authors.lastname: Koul
authors.forename: Ruijun
authors.initials: R
authors.lastname: Shen
authors.forename: Sherry
authors.initials: S
authors.lastname: Bergh
authors.forename: Yiling
authors.initials: Y
authors.lastname: Lu
authors.forename: John F
authors.initials: JF
authors.lastname: de Groot
authors.forename: Ta Jen
authors.initials: TJ
authors.lastname: Liu
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.forename: W K Alfred
authors.initials: WK
authors.lastname: Yung
mesh_terms: D015153:Blotting, Western; D002453:Cell Cycle; D002455:Cell Division; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005109:Extracellular Matrix / Q000378:metabolism; D005353:Fibronectins / Q000737:chemistry / Q000378:metabolism; D016195:G2 Phase; D005909:Glioblastoma / Q000201:enzymology* / Q000473:pathology*; D005910:Glioma / Q000628:therapy; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012694:Serine / Q000737:chemistry; D015398:Signal Transduction; D013912:Threonine / Q000737:chemistry; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D019096:Vitronectin / Q000737:chemistry / Q000378:metabolism; D000099200:Scaffold Protein ILK
chemical_list: D004791:Enzyme Inhibitors; D005353:Fibronectins; D020778:Matrix Metalloproteinase 2; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D012694:Serine; D013912:Threonine; D042461:Vascular Endothelial Growth Factor A; D019096:Vitronectin; D000099200:Scaffold Protein ILK