title: Integrin-linked kinase regulates senescence in an Rb-dependent manner in cancer cell lines.
abstract: Anti-integrin-linked kinase (ILK) therapies result in aberrant mitosis including altered mitotic spindle organization, centrosome declustering and mitotic arrest. In contrast to cells that expressed the retinoblastoma tumor suppressor protein Rb, we have shown that in retinoblastoma cell lines that do not express Rb, anti-ILK therapies induced aberrant mitosis that led to the accumulation of temporarily viable multinucleated cells. The present work was undertaken to: 1) determine the ultimate fate of cells that had survived anti-ILK therapies and 2) determine whether or not Rb expression altered the outcome of these cells. Our data indicate that ILK, a chemotherapy drug target is expressed in both well-differentiated, Rb-negative and relatively undifferentiated, Rb-positive retinoblastoma tissue. We show that small molecule targeting of ILK in Rb-positive and Rb-deficient cancer cells results in increased centrosomal declustering, aberrant mitotic spindle formation and multinucleation. However, anti-ILK therapies in vitro have different outcomes in retinoblastoma and glioblastoma cell lines that depend on Rb expression. TUNEL labeling and propidium iodide FACS analysis indicate that Rb-positive cells exposed to anti-ILK therapies are more susceptible to apoptosis and senescence than their Rb-deficient counterparts wherein aberrant mitosis induced by anti-ILK therapies exhibit mitotic arrest instead. These studies are the first to show a role for ILK in chemotherapy-induced senescence in Rb-positive cancer lines. Taken together these results indicate that the oncosuppressive outcomes for anti-ILK therapies in vitro, depend on the expression of the tumor suppressor Rb, a known G1 checkpoint and senescence regulator.
authors.affiliation: a Department of Biology ; Trinity Western University ; Langley , British Columbia , Canada.
authors.forename: Rose
authors.initials: R
authors.lastname: Duminuco
authors.affiliation: a Department of Biology ; Trinity Western University ; Langley , British Columbia , Canada.
authors.forename: Jake W
authors.initials: JW
authors.lastname: Noble
authors.affiliation: a Department of Biology ; Trinity Western University ; Langley , British Columbia , Canada.
authors.forename: Joseph
authors.initials: J
authors.lastname: Goody
authors.affiliation: b Vancouver Prostate Center; Vancouver Coastal Health Research Institute ; Vancouver , British Columbia.
authors.forename: Manju
authors.initials: M
authors.lastname: Sharma
authors.affiliation: d Department of Ophthalmology ; Schepens Eye Research Institute; Harvard Medical School ; Boston , Massachusetts , United States of America.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Ksander
authors.affiliation: c Department of Cellular and Physiological Sciences ; University of British Columbia ; Canada.
authors.forename: Calvin D
authors.initials: CD
authors.lastname: Roskelley
authors.affiliation: b Vancouver Prostate Center; Vancouver Coastal Health Research Institute ; Vancouver , British Columbia.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Cox
authors.affiliation: a Department of Biology ; Trinity Western University ; Langley , British Columbia , Canada.|e Adjunct in the Department of Molecular Biology and Biochemistry ; Simon Fraser University ; Burnaby , British Columbia , Canada.
authors.forename: Julia
authors.initials: J
authors.lastname: Mills
mesh_terms: D001391:Azo Compounds / Q000494:pharmacology; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D055785:Gene Knockdown Techniques; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D011720:Pyrazoles / Q000494:pharmacology; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000099200:Scaffold Protein ILK
chemical_list: D001391:Azo Compounds; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011720:Pyrazoles; D016160:Retinoblastoma Protein; D000099200:Scaffold Protein ILK; C552362:QLT 0267
keywords: Integrin-linked kinase; cancer; centrosome declustering; mitotic arrest; multinucleation; multipolar mitosis; retinoblastoma; senescence