Inhibition of Integrin-Linked Kinase (ILK) Suppresses Activation of Protein Kinase B/Akt and Induces Cell Cycle Arrest and Apoptosis of PTEN-Mutant Prostate Cancer Cells

• Published in: Proceedings of the National Academy of Sciences - PNAS 2000-03, Vol.97 (7), p.3207-3212
• Main Authors: Persad, Sujata, Attwell, Sarah, Gray, Virginia, Delcommenne, Marc, Troussard, Armelle, Sanghera, Jasbinder, Dedhar, Shoukat
• Format: Article
• Language: English
• Subjects: Akt protein; Antibodies; Apoptosis; Biological Sciences; Cell Cycle; Cell lines; Cellular biology; chromosome 10; Complementary DNA; Enzyme Activation; Epithelial cells; Genes; Humans; integrin-linked kinase; Male; Mutation; Phosphoric Monoester Hydrolases - genetics; Phosphorylation; Prostate cancer; prostate carcinoma; Prostatic Neoplasms - enzymology; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; protein kinase B; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein Serine-Threonine Kinases - metabolism; Proteins; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; PTEN gene; PTEN Phosphohydrolase; Transfection; Tumor Cells, Cultured; Tumor Suppressor Proteins; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.060579697

PTEN is a tumor suppressor gene located on chromosome 10q23 that encodes a protein and phospholipid phosphatase. Somatic mutations of PTEN are found in a number of human malignancies, and loss of expression, or mutational inactivation of PTEN, leads to the constitutive activation of protein kinase B (PKB)/Akt via enhanced phosphorylation of Thr-308 and Ser-473. We recently have demonstrated that the integrin-linked kinase (ILK) can phosphorylate PKB/Akt on Ser-473 in a phosphoinositide phospholipid-dependent manner. We now demonstrate that the activity of ILK is constitutively elevated in a serum- and anchorage-independent manner in PTEN-mutant cells, and transfection of wild-type (WT) PTEN into these cells inhibits ILK activity. Transfection of a kinase-deficient, dominant-negative form of ILK or exposure to a small molecule ILK inhibitor suppresses the constitutive phosphorylation of PKB/Akt on Ser-473, but not on Thr-308, in the PTEN-mutant prostate carcinoma cell lines PC-3 and LNCaP. Transfection of dominant-negative ILK and WT PTEN into these cells also results in the inhibition of PKB/Akt kinase activity. Furthermore, dominant-negative ILK or WT PTEN induces G1phase cycle arrest and enhanced apoptosis. Together, these data demonstrate a critical role for ILK in PTEN-dependent cell cycle regulation and survival and indicate that inhibition of ILK may be of significant value in PTEN-mutant tumor therapy.