title: Integrin-linked kinase is a potential therapeutic target for anaplastic thyroid cancer.
abstract: We investigated integrin-linked kinase (ILK), a focal adhesion serine-threonine protein kinase, as a new molecular target for treating anaplastic thyroid cancer. ILK mediates cell growth and survival signals and is overexpressed in a number of cancers. Therefore, we hypothesized that inhibition of ILK leads to growth arrest and apoptosis of thyroid cancer cells. According to Western blotting, the level of ILK protein was highly expressed in one papillary (NPA187) and four of five (Hth74, DRO, ARO, KAT4, and K4) anaplastic thyroid cancer cell lines. Immunohistochemical analysis of a human tissue microarray revealed that ILK was highly expressed in anaplastic thyroid cancer but not in normal human thyroid tissue. Treating thyroid cancer cell lines with a new ILK inhibitor, QLT0267, inhibited epidermal growth factor-induced phosphorylation of AKT, inhibited cell growth, and induced apoptosis in the NPA187, DRO, and K4 cell lines. QLT0267 also inhibited the kinase activity of immunoprecipitated ILK in four of five cell lines. Tumor volumes in mice treated with QLT0267 were significantly reduced compared with those in untreated mice. In immunohistochemical studies, QLT0267 suppressed phosphorylated p-AKT and angiogenesis (i.e., reduced mean vascular density) and induced apoptosis in both tumor cells and tumor-associated endothelial cells of the thyroid DRO xenografts. In summary, we found that ILK expression and activity were elevated in human anaplastic thyroid cancer and ILK inhibition led to growth arrest and apoptosis in vitro and in vivo. Our results provide preliminary evidence that ILK is a potential therapeutic target for treating anaplastic thyroid cancer.
authors.affiliation: Department of Head and Neck Surgery, The University of Texas M.D. Anderson Cancer Center, Unit 441, 1515 Holcombe Boulevard, Houston, TX 77030-4009, USA. jmyers@mdanderson.org.
authors.forename: Maher N
authors.initials: MN
authors.lastname: Younes
authors.forename: Seungwon
authors.initials: S
authors.lastname: Kim
authors.forename: Orhan G
authors.initials: OG
authors.lastname: Yigitbasi
authors.forename: Mahitosh
authors.initials: M
authors.lastname: Mandal
authors.forename: Samar A
authors.initials: SA
authors.lastname: Jasser
authors.forename: Yasemin
authors.initials: Y
authors.lastname: Dakak Yazici
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Schiff
authors.forename: Adel
authors.initials: A
authors.lastname: El-Naggar
authors.forename: Benjamin N
authors.initials: BN
authors.lastname: Bekele
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Myers
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis; D042783:Endothelial Cells / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D013964:Thyroid Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000201:enzymology*; D046888:Tissue Array Analysis; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D000099200:Scaffold Protein ILK
chemical_list: D000970:Antineoplastic Agents; D004815:Epidermal Growth Factor; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D000099200:Scaffold Protein ILK; C494918:AKT1 protein, human