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.