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Insulin-like Growth Factor-I–Dependent Up-regulation of ZEB1 Drives Epithelial-to-Mesenchymal Transition in Human Prostate Cancer Cells

¹ Department of Hematology and Oncology, Winship Cancer Institute, Departments of ² Molecular Urology and Therapeutics, ³ Pathology and Urology, ⁴ Biostatistics, and ⁵ Biomedical Engineering, Emory University; ⁶ Department of Biological Sciences, Clark Atlanta University; ⁷ Department of Material Sciences Engineering, Georgia Institute of Technology, Atlanta, Georgia

Requests for reprints: Ruth M. O'Regan, Winship Cancer Institute, Emory University School of Medicine, 1701 Uppergate Drive, WCI Building C, Atlanta, GA 30322. Phone: 404-778-5994; Fax: 404-778-5530; E-mail: Ruth.ORegan{at}emoryhealthcare.org.

Key Words: IGF-I • ZEB1 • EMT • ARCaP • Prostate Cancer

The epithelial-to-mesenchymal transition (EMT) is crucial for the migration and invasion of many epithelial tumors, including prostate cancer. Although it is known that ZEB1 overexpression promotes EMT primarily through down-regulation of E-cadherin in a variety of cancers, the soluble ligands responsible for the activation of ZEB1 have yet to be identified. In the present study, we investigated the role of insulin-like growth factor-I (IGF-I) in the regulation of ZEB1 during EMT associated with prostate tumor cell migration. We found that ZEB1 is expressed in highly aggressive prostate cancer cells and that its expression correlates directly with Gleason grade in human prostate tumors (P < 0.001). IGF-I up-regulates ZEB1 expression in prostate cancer cells exhibiting an epithelial phenotype. In prostate cancer cells displaying a mesenchymal phenotype, ZEB1 inhibition reverses the suppression of E-cadherin protein and down-regulates the expression of the mesenchymal markers N-cadherin and fibronectin. Furthermore, ZEB1 blockade decreases migratory and invasive potential in ARCaP_M compared with the control. These results identify ZEB1 as a key transcriptional regulator of EMT in prostate cancer and suggest that the aberrant expression of ZEB1 in prostate cancer cells occurs in part in response to IGF-I stimulation. [Cancer Res 2008;68(7):2479–88]

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				M. M. Chitnis, J. S.P. Yuen, A. S. Protheroe, M. Pollak, and V. M. Macaulay The Type 1 Insulin-Like Growth Factor Receptor Pathway Clin. Cancer Res., October 15, 2008; 14(20): 6364 - 6370. [Abstract] [Full Text] [PDF]

				Correction: ZEB1 Activation in Prostate Cancer Cancer Res., May 15, 2008; 68(10): 4012 - 4012. [Full Text] [PDF]