Carcinogenesis Advance Access published online on June 29, 2005
Carcinogenesis, doi:10.1093/carcin/bgi170
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1 Department of Urology, University of Rochester, Rochester, NY 14642, USA; Department of Chemical Engineering, University of Rochester, Rochester, NY 14642, USA
* To whom correspondence should be addressed. Inhibition of invasion and metastasis has become a new approach for treatment of advanced prostate cancer in which secondary hormone therapy has failed. Accumulating evidence indicates that 1 The first two authors contributed equally to this article
Received March 1, 2005
Revised June 19, 2005
Accepted June 21, 2005
CANCER BIOLOGY
1
, 25-dihydroxyvitamin D3 inhibits prostate cancer cell invasion via modulation of selective proteases
2 Graduate Institute of Medical Sciences, Department of Urology, Taipei Medical University, Taipei 110, Taiwan
3 Department of Urology, University of Rochester, Rochester, NY 14642, USA
Yi-Fen Lee, E-mail: yifen_lee{at}urmc.rochester.edu
Abstract 
, 25-dihydroxyvitamin D3 (1,25-VD) suppresses prostate cancer progression by inhibition of tumor growth and metastasis. However, the detailed mechanisms underlying these effects remain to be determined. Here we used the in vitro cell invasion assay to demonstrate that 1,25-VD inhibits the invasive ability of human prostate cancer cell lines, LNCaP, PC-3, and DU 145. Three major groups of proteases, the matrix metalloproteinases (MMPs), the plasminogen activators (PAs), and the cathepsins (CPs), that are involved in tumor invasion were then examined for changes in activity and expression after 1,25-VD treatment. We found that 1,25-VD decreased MMP-9 and CPs, but not PAs activities while it increased their counterparts, tissue inhibitors of metalloproteinase-1 (TIMP-1) and cathepsin inhibitors (CPIs) activity. Mechanistic studies showed that 1,25-VD didn't suppress MMP-9 expression at the transcriptional level, but reduced its mRNA stability. In addition, 1,25-VD increased AP-1 complexes binding to TIMP-1 promoter, which contributed to the enhancement of TIMP-1 gene activity, and thus resulted in inhibition of MMP activity and tumor invasion. These findings support the idea that vitamin D-based therapies might be beneficial in the management of advanced prostate cancer, especially among patients who have higher MMP-9 and CPs activities.
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