AJTR Copyright © 2009-All rights reserved. Published by e-Century Publishing Corporation, Madison, WI 53711
Am J Transl Res 2010;2(1):88-94

Original Article
Phenyl-methylene hydantoins alter CD44-specific ligand binding
of benign and malignant prostate cells and suppress CD44 isoform

Kui Yang, Yaqiong Tang, Kenneth A. Iczkowski

1From the Department of Pathology, University of Colorado Denver Health Science Center, Aurora, CO

Received October 10, 2009; accepted November 10, 2009; available online January 1, 2009

Abstract: Dysregulated CD44 expression is a feature of most human cancers, including prostate cancer (PCa).  
PCa loses expression of CD44 standard (CD44s) which is present in benign epithelium, and overexpresses a
novel splice variant isoform, CD44v7-10, specifically facilitating fibronectin binding and invasion.  Naturally-
occurring or synthetic phenyl-methylene hydantoin (PMH) and S-ethyl PMH (S-PMH) can reportedly augment cell-
cell adhesion, and reduce invasion and growth of PCa.  Benign BPH-1 and malignant PC-3M prostate cells were
treated with PMH or S-PMH for 36 h and cells were harvested.  Cell adhesion assays were carried out.  Cancer
cells’ expression of total CD44 and CD44v7-10 were tested by western blot analysis and real-time RT-PCR.  
Compared to BPH-1 or PC-3M cells treated with vehicle only, PMH-or S-PMH-treated benign and malignant cells
had decreased adhesion to hyaluronan (p=0.001 to 0.007) and fibronectin (p<0.001 to 0.047).  Both compounds
decreased PCa expression of CD44 total mRNA (representing mostly CD44s, to 0.076±0.033 and 0.254±0.123 of
control) and CD44v7-10 (to 0.386±0.279 and 0.115±0.037 of control).  S-PMH but not PMH decreased CD44 total
protein, while both decreased CD44v7-10 protein.  Both hydantoins lowered β-catenin, as reported previously.  
Both only slightly decreased β1-integrin, the definitive receptor for fibronectin.  In conclusion, the ability of PMH
and S-PMH to decrease hyaluronan adhesion appears to be mediated through decreased CD44s, while the
decrease in fibronectin adhesion correlates with, and may be mediated by, decreased CD44v7-10.   

Key words: Alternate splicing; CD44; hydantoin; phenyl-methylene hydantoin; prostate cancer; hyaluronan;

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Address all correspondence to:
Kenneth A. Iczkowski, MD
Pathology—Campus Mail Stop 8104
12800 E. 19th Avenue
Aurora, CO  80045.
Tel: 303-724-0155, Fax: 303-724-3712