Carcinogenesis Advance Access originally published online on February 20, 2009
Carcinogenesis 2009 30(5):808-817; 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, 1300 University Avenue, MSC-25B, Madison, WI 53706, USA
1 Molecular and Environmental Toxicology Center
2 School of Pharmacy, University of Wisconsin, Madison, WI 53706
3 Department of Urology, 2045 Lied Biomedical Research Facility, University of Kansas Medical Center, Mail Stop 3035, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA
* To whom correspondence should be addressed. Tel: +1 608 263 3927; Fax: +1 608 263 5223;Email: hmukhtar{at}wisc.edu
Lupeol, a dietary triterpene, was shown to decrease serum prostate-specific antigen 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, tissue inhibitor of metalloproteinases-3, cyclin D1 and matrix metalloproteinase (MMP)-2 that 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 that 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 glycogen synthase kinase 3 beta (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 T Cell Factor (TCF) responsive element (marker for β-catenin signaling) in pTK-TCF-Luc-transfected cells and (5) 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 small interfering RNA transfection and GSK3β activity is blocked. Collectively, these data suggest the multitarget 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.
Abbreviations: BIO, (2'Z,3'E)-6-bromoindirubin-3'-oxime; CaP, prostate cancer; GSK3β, glycogen synthase kinase 3 beta; IGFBP, insulin-like growth factor binding protein; MMP, matrix metalloproteinase; siRNA, small interfering RNA; TCF, T Cell Factor; TIMP, tissue inhibitor of metalloproteinases
These authors contributed equally to this work. Received December 2, 2008; revised January 28, 2009; accepted February 5, 2009.