Journal
ONCOGENE
Volume 24, Issue 22, Pages 3596-3605Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1208427
Keywords
glioblastomas; integrin-linked kinase; brain cancer
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The tumor suppressor gene phosphatase and tensin homologue ( PTEN) regulates the phosphatidylinositol-3'- kinase ( PI3K) signaling pathway and has been shown to correlate with poor prognosis in high- grade astrocytomas when mutational inactivation or loss of the PTEN gene occurs. PTEN mutation leads to constitutive activation of protein kinase B ( PKB)/ Akt with phosphorylation at the PKB/ Akt sites Thr- 308 and Ser- 473. Integrin- linked kinase ( ILK) has been shown to regulate PKB/ Akt activity with the loss of PTEN in prostate cancer. We now demonstrate that ILK activity regulates PKB/ Akt activity in glioblastoma cells. The activity of ILK is constitutively elevated in a serum- independent manner in PTEN mutant cells, and transfection of wild- type PTEN under the control of an inducible promoter into mutant PTEN cells inhibits ILK activity. Transfection of ILK antisense ( ILKAS) or exposure to a small- molecule ILK inhibitor suppresses the constitutive phosphorylation of PKB/ Akt on Ser- 473 in PTEN- mutant glioblastoma cell lines. In addition, the delivery of ILKAS to PTEN-negative glioblastoma cells resulted in apoptosis. Rag- 2M mice bearing established ( similar to 100 mg) human U87MG glioblastoma tumors, treated QD x 5 for 3 consecutive weeks with ILKAS ( i. p. 5 mg/ kg), exhibited stable disease with <= 7% increase in tumor volume over the 3- week course of treatment. In contrast, animals treated with an oligonucleotide control or saline exhibited a > 100% increase in tumor volume over the same time period. Our initial results indicate that therapeutic strategies targeting ILK maybe beneficial in the treatment of glioblastomas.
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