Integrin-linked kinase is a potential therapeutic target for anaplastic thyroid cancer

Maher N. Younes, Seungwon Kim, Orhan G. Yigitbasi, Mahitosh Mandal, Samar A. Jasser, Yasemin Dakak Yazici, Bradley A. Schiff, Adel El-Naggar, Benjamin N. Bekele, Gordon Mills, Jeffrey N. Myers

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1146-1156
Number of pages11
JournalMolecular Cancer Therapeutics
Volume4
Issue number8
DOIs
StatePublished - Aug 1 2005
Externally publishedYes

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Apoptosis
Therapeutics
Cell Line
Growth
Thyroid Neoplasms
Thyroid Gland
Anaplastic Thyroid Carcinoma
integrin-linked kinase
Focal Adhesion Protein-Tyrosine Kinases
Neoplasms
Protein-Serine-Threonine Kinases
Tumor Burden
Epidermal Growth Factor
Heterografts
Blood Vessels
Cell Survival
Phosphotransferases
Endothelial Cells
Western Blotting
Phosphorylation

ASJC Scopus subject areas

  • Oncology
  • Drug Discovery
  • Pharmacology

Cite this

Younes, M. N., Kim, S., Yigitbasi, O. G., Mandal, M., Jasser, S. A., Yazici, Y. D., ... Myers, J. N. (2005). Integrin-linked kinase is a potential therapeutic target for anaplastic thyroid cancer. Molecular Cancer Therapeutics, 4(8), 1146-1156. https://doi.org/10.1158/1535-7163.MCT-05-0078

Integrin-linked kinase is a potential therapeutic target for anaplastic thyroid cancer. / Younes, Maher N.; Kim, Seungwon; Yigitbasi, Orhan G.; Mandal, Mahitosh; Jasser, Samar A.; Yazici, Yasemin Dakak; Schiff, Bradley A.; El-Naggar, Adel; Bekele, Benjamin N.; Mills, Gordon; Myers, Jeffrey N.

In: Molecular Cancer Therapeutics, Vol. 4, No. 8, 01.08.2005, p. 1146-1156.

Research output: Contribution to journalArticle

Younes, MN, Kim, S, Yigitbasi, OG, Mandal, M, Jasser, SA, Yazici, YD, Schiff, BA, El-Naggar, A, Bekele, BN, Mills, G & Myers, JN 2005, 'Integrin-linked kinase is a potential therapeutic target for anaplastic thyroid cancer', Molecular Cancer Therapeutics, vol. 4, no. 8, pp. 1146-1156. https://doi.org/10.1158/1535-7163.MCT-05-0078
Younes, Maher N. ; Kim, Seungwon ; Yigitbasi, Orhan G. ; Mandal, Mahitosh ; Jasser, Samar A. ; Yazici, Yasemin Dakak ; Schiff, Bradley A. ; El-Naggar, Adel ; Bekele, Benjamin N. ; Mills, Gordon ; Myers, Jeffrey N. / Integrin-linked kinase is a potential therapeutic target for anaplastic thyroid cancer. In: Molecular Cancer Therapeutics. 2005 ; Vol. 4, No. 8. pp. 1146-1156.
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AU - Yazici, Yasemin Dakak

AU - Schiff, Bradley A.

AU - El-Naggar, Adel

AU - Bekele, Benjamin N.

AU - Mills, Gordon

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AB - 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.

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