1. ¹Department of Advanced Therapeutics, BC Cancer Agency, Vancouver, BC, Canada
2. ²Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
3. ³Department of Medical Oncology, BC Cancer Agency, Vancouver, BC, Canada
4. ⁴Department of Medicinal Chemistry, QLT Inc, Vancouver, BC, Canada
5. ⁵Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada
6. ⁶Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada
7. ⁷Department of Cancer Genetics, BC Cancer Agency, Vancouver, BC, Canada

Correspondence: LA Edwards, Department of Advanced Therapeutics, BC Cancer Agency, BC Cancer Research Centre, 601 West 10th Ave, Vancouver, BC, Canada. E-mail: ledwards@bccrc.ca

Received 1 November 2004; Revised 2 December 2004; Accepted 2 December 2004; Published online 21 March 2005.

Abstract

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 (100 mg) human U87MG glioblastoma tumors, treated QD 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 may be beneficial in the treatment of glioblastomas.