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Cdc37 Enhances Proliferation and Is Necessary for Normal Human Prostate Epithelial Cell Survival¹

Department of Surgery, Division of Urology, University of Wisconsin Medical School, Molecular and Environmental Toxicology and the University of Wisconsin Comprehensive Cancer Center, Madison, Wisconsin 53972

Cdc37 is a co-chaperone protein that recruits several immature client kinases to Hsp90 for proper folding. Cdc37 up-regulation is a common early event in localized human prostate cancer. Although targeted overexpression in mice leads to prostate epithelial cell hyperplasia, the effect of Cdc37 dysregulation in human prostate cells is unclear. In this study, we examine the role of Cdc37 in the growth regulation of normal prostate epithelial cells using a unique human model system. We demonstrate that Cdc37 overexpression drives proliferation, whereas loss of Cdc37 function arrests growth and leads to apoptosis. With increased Cdc37 expression, molecular analysis of Cdc37 client pathways demonstrates enhanced Raf-1 activity, greater Cdk4 levels, and reduced expression of the cyclin-dependent kinase inhibitor p16/CDKN2. To further investigate these downstream pathways, enhanced Raf-1 or Cdk4 activities were selectively induced in human prostate epithelial cells. Raf-1 activation inhibited proliferation and generated an enlarged, flattened morphology. Induction of Cdk4 activity using cyclin D1 overexpression, however, was sufficient to promote proliferation. These data indicate that Cdc37 induces proliferation and is critical for survival in human prostate epithelial cells. These alterations in cell division and survival may be important in the development and progression of early prostate cancer.

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