PDF(Pubmed)
Abstract：
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.
摘要：
在癌细胞中，整合素连接激酶（ILK）的抑制会增加中心体的去细胞，从而导致有丝分裂停滞和细胞死亡。然而，并非所有的癌细胞都对单独的抗ILK治疗敏感。我们研究了针对ILK和另一种致癌激酶的联合药物策略，Abelson激酶(ABL)。药物浓度活力测定(即，MTT测定）表明，与单独的ILK药物QLT-0267相比，ILK和ABL抑制剂的组合降低了胶质母细胞瘤细胞的活力。与单独的QLT-0267相比,组合策略还增加了异常有丝分裂和细胞死亡。从有丝分裂停滞的增加可以明显看出这一点，凋亡和FAC分析后的亚G1峰。体外，ILK和ABL定位于中心体，推定的ILK激酶结构域对于这种定位很重要。胞质ABL水平的增加与其转化能力有关。ILK抑制剂对存活的影响与其降低细胞溶质ABL水平和抑制ABL在胶质母细胞瘤细胞中的有丝分裂中心体定位的能力相关。ILK抑制剂对ABL中心体定位的作用被蛋白酶体抑制剂MG132(一种抑制ABL降解的药物)逆转。这些结果表明,ILK调节有丝分裂中心体处的ABL,并且靶向ILK和ABL的组合治疗在降低分裂的成胶质细胞瘤细胞的存活方面比单独的QLT-0267更有效。
