Lupeol inhibits proliferation of human prostate cancer cells by targeting beta-catenin signaling.
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 beta-catenin signaling that is highly aberrant in CaP patients. Lupeol treatment significantly (1) reduced levels of beta-catenin in the cytoplasmic and nuclear fractions, (2) modulated expression levels of glycogen synthase kinase 3 beta (GSK3beta)-axin complex (regulator of beta-catenin stability), (3) decreased the expression level and enzymatic activity of MMP-2 (downstream target of beta-catenin), (4) reduced the transcriptional activation of T Cell Factor (TCF) responsive element (marker for beta-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 beta-catenin degradation were significantly reduced in CaP cells where axin is knocked down through small interfering RNA transfection and GSK3beta activity is blocked. Collectively, these data suggest the multitarget efficacy of Lupeol on beta-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.
Saleem
Mohammad
M
Department of Dermatology, University of Wisconsin, 1300 University Avenue, MSC-25B, Madison, WI 53706, USA.
Murtaza
Imtiyaz
I
Tarapore
Rohinton S
RS
Suh
Yewseok
Y
Adhami
Vaqar Mustafa
VM
Johnson
Jeremy James
JJ
Siddiqui
Imtiaz Ahmad
IA
Khan
Naghma
N
Asim
Mohammad
M
Hafeez
Bilal Bin
BB
Shekhani
Mohammed Talha
MT
Li
Benyi
B
Mukhtar
Hasan
H
D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects*; D019938:Cyclin D1 / Q000235:genetics; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000187:drug effects / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D053978:Pentacyclic Triterpenes; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics; D014315:Triterpenes / Q000494:pharmacology*; D051176:beta Catenin / Q000502:physiology*; D000094042:Lupanes
D000893:Anti-Inflammatory Agents; D019938:Cyclin D1; D020778:Matrix Metalloproteinase 2; D053978:Pentacyclic Triterpenes; D019717:Tissue Inhibitor of Metalloproteinase-3; D014315:Triterpenes; D051176:beta Catenin; C010480:lupeol; D000094042:Lupanes