Carcinogenesis Advance Access published online on January 23, 2004
Carcinogenesis, doi:10.1093/carcin/bgh095
© 2004 by Oxford University Press
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MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
1 Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294
* Corresponding author. E-mail: skatiyar{at}uab.edu.
Received 11 November 2003
; revised 22 December 2003
; accepted 14 January 2004
Prostate cancer (PCA) is the second most frequently diagnosed and leading cause of cancer-related deaths in men in the USA. The recognition that matrix metalloproteinases (MMPs) facilitate tumor cell invasion and metastasis of PCA has led to the development of MMP inhibitors as cancer therapeutic agents. As part of our efforts to develop newer and effective chemopreventive agents for PCA, we evaluated the effect of proanthocyanidins from grape seeds (GSP) on metastasis-specific MMP-2 and -9 in human prostate carcinoma DU145 cells by employing Western blot and gelatinolytic zymography. Treatment of GSP dose-dependently inhibited cell proliferation (15-100% by 5-80µg/ml of GSP), viability (30-80% by 20-80 µg/ml of GSP) and fibroblast conditioned medium (FCM)-induced expression of MMP-2 and -9 in DU145 cells. Since the signaling cascade of mitogen-activated protein kinases (MAPK) have been shown to regulate the expression of MMPs in tumor cells, we found that the treatment of DU145 cells with GSP (20-80 µg/ml) resulted in marked inhibition of FCM-induced phosphorylation of ERK1/2 and p38 but had little effect on JNK under similar experimental conditions. GSP treatment (20-80 µg/ml) to DU145 cells also dosedependently inhibited FCM-induced activation of NF
Proanthocyanidins from grape seeds inhibit expression of matrix metalloproteinases in human prostate carcinoma cells which is associated with the inhibition of activation of MAPK and NF
B
2 Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294; Department of Environmental Health Sciences, University of Alabama at Birmingham, Birmingham, AL 35294; Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294
B concomitantly inhibition of MMP-2 and MMP-9 expression in the same system. Additionally, the treatment of inhibitors of MEK (PD98059) and p38 (SB203580) to DU145 cells resulted in reduction of FCM-induced phosphorylation of ERK1/2 and p38 concomitantly marked reduction in MMP-2 and -9 expressions. In further studies, treatment of androgen-sensitive LNCaP cells with a synthetic androgen R1881 resulted in an increase of MMP-2 and -9, which were completely abrogated in the presence of GSP (20-60µg/ml). These data suggest that inhibition of metastasis-specific MMPs in tumor cells by GSP is associated with the inhibition of activation of MAPK and NFB pathways, and thus providing the molecular basis for the development of GSP as a novel chemopreventive agent for both androgen-sensitive and -insensitive prostate cancer therapies.
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