Combination Effects of Integrin-linked Kinase and Abelson Kinase Inhibition on Aberrant Mitosis and Cell Death in Glioblastoma Cells

Simple Summary Glioblastomas are common and aggressive brain tumours that exist in adults and children. Currently, there are no effective treatment strategies. Most cancer cells, including glioblastoma cells, exhibit abnormal centrosomes, the key cellular machinery that controls division. Cancer-causing proteins such as integrin-linked kinase and Abelson kinase occur at abnormal centrosomes and these proteins are chemotherapeutic drug targets. In this study, we use a novel cancer drug combination strategy to target these cancer-causing proteins in vitro. We find that a drug that targets integrin-linked kinase also affects Abelson kinase levels and its localization to the centrosome in dividing glioblastoma cells. Moreover, exposure of glioblastoma cells to chemotherapeutic drugs in combination significantly increased aberrant mitotic division and cell death over individual inhibitors alone. These results indicate that integrin-linked kinase regulates Abelson kinase at mitotic centrosomes and combination drug treatment strategies are more effective than individual inhibitors alone at increasing the lethal mitotic division of dividing glioblastoma cells. In cancer cells, inhibition of integrin-linked kinase (ILK) increases centrosome declustering causing mitotic arrest and cell death. Yet, not all cancer cells are susceptible to anti-ILK treatment alone. We investigate a combination drug strategy targeting ILK and another oncogenic kinase, Abelson kinase (ABL). Drug-concentration viability assays (i.e., MTT assays) indicate that ILK and ABL inhibitors in combination decreased the viability of glioblastoma cells over the ILK drug QLT-0267 alone. Combination strategies also increased aberrant mitoses and cell death over QLT-0267 alone. This was evident from an increase in mitotic arrest, apoptosis and a sub-G1 peak following FAC analysis. In vitro, ILK and ABL localized to the centrosome and the putative ILK kinase domain was important for this localization. Increased levels of cytosolic ABL are associated with its transformative abilities. ILK inhibitor effects on survival correlated with its ability to decrease cytosolic ABL levels and inhibit ABL's localization to mitotic centrosomes in glioblastoma cells. ILK inhibitor effects on ABL's centrosomal localization were reversed by the proteasomal inhibitor MG132 (a drug that inhibits ABL degradation). These results indicate that ILK regulates ABL at mitotic centrosomes and that combination treatments targeting ILK and ABL are more effective then QLT-0267 alone at decreasing the survival of dividing glioblastoma cells.