Carcinogenesis Advance Access published online on February 20, 2009
Carcinogenesis, doi:10.1093/carcin/bgp044
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Lupeol Inhibits Proliferation of Human Prostate Cancer Cells by Targeting β-catenin Signaling
Department of Dermatology, University of Wisconsin, Madison, WI 53706
2 Molecular and Environmental Toxicology Center, University of Wisconsin, Madison, WI
3 School of Pharmacy, University of Wisconsin, Madison, WI
4 The University of Kansas Medical Center, Kansas City, Kansas
Address Correspondence to: Hasan Mukhtar (Ph.D.), Director and Vice Chair of Research, Department of Dermatology, University of Wisconsin, 1300 University Avenue, MSC-25B, Madison, Wisconsin, 53706, Phone: 608-263-3927, E-mail: hmukhtar{at}wisc.edu
Lupeol ,a dietary triterpene, was shown to decrease serum-PSA levels and inhibit the tumorigenicity of prostate cancer (CaP) cells in vivo. Here we show that Lupeol inhibits the proliferative potential of CaP cells and delineated its mechanism of action. Employing a focused microarray of human CaP-associated genes, we found that Lupeol significantly modulates the expression level of genes such as ERBB2, TIMP3, cyclin D1 and MMP-2 which are known to be associated with proliferation and survival. A common feature of these genes is that all of them are known to either regulate or act as downstream target of β-catenin signaling which is highly aberrant in CaP patients. Lupeol treatment significantly (1) reduced levels of β-catenin in the cytoplasmic and nuclear fractions, (2) modulated expression levels of GSK3β/Axin complex (regulator of β-catenin stability), (3) decreased the expression level and enzymatic activity of MMP-2 (downstream target of β-catenin), (4) reduced the transcriptional activation of TCF responsive element (marker for β-catenin signaling) in pTK-TCF-Luc-transfected cells, and (4) decreased the transcriptional activation of MMP-2 gene in pGL2-MMP-2-Luc-transfected cells. Effects of Lupeol treatment on β-catenin degradation were significantly reduced in CaP cells where axin-is knocked down through siRNA transfection and GSK3β activity is blocked. Collectively these data suggest the multi-target efficacy of Lupeol on β-catenin signaling network thus resulting in the inhibition CaP cell proliferation. We suggest that Lupeol could be developed as an agent for chemoprevention as well as chemotherapy of human CaP.
1 Both authors equally contributed to this work.
Received December 2, 2008; revised January 28, 2009; accepted February 5, 2009.