Lupeol inhibits proliferation of human prostate cancer cells by targeting  -catenin signaling

Abstract

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.

Regulation of neuroendocrine differentiation by AKT/hnRNPK/AR/β‐catenin signaling in prostate cancer cells

“…23,24 Beta-catenin, a component of the Wnt signaling pathway, induces NED when overexpressed in LNCaP cells 24 and blockade of b-catenin signaling suppresses prostate carcinogenesis in TRAMP mice and tumorigenicity of prostate cancer cells in vivo. 25,26 Since the reduction of AR expression is consistent with the evidence that Wnt signaling increases Akt phosphorylation that in turn promotes AR degradation through a proteosomal pathway, 27 we determined the expression levels of b-catenin in our TRAMP specimens. We found high levels of b-catenin in NE samples (Fig.…”

Aegle marmelos (L.) Correa (Bael) and Its Phytochemicals in the Treatment and Prevention of Cancer

“…25 The ErbB2 (Her2) proto-oncogene encodes a receptor tyrosine kinase, which is frequently amplified and overexpressed in many human tumors, such as breast, ovarian, prostate, non-small cell lung cancers, and cancers of the head and neck. ErbB2 is a cell membrane surface-bound receptor with intrinsic tyrosine kinase activity and is involved in the signal transduction pathways.…”

Chemotherapeutic potiential of Lupeol and its analogue (oxime) on human mammary cancer cell line (MCF-7)

“…Many of the agents that induce apoptosis are oxidants or stimulators of cellular oxidative metabolism, while many inhibitors of apoptosis show antioxidant activity [26] . Indeed, factors that induce oxidative stress, such as ROS production, lipid per oxidation, down regulation of the antioxidant defenses characterized by reduced glutathione levels, and reduced transcription of superoxide dismutase, catalase, and thio redox in have been observed in some apoptotic processes [27] . Interestingly, we observed significantly increased in lipid peroxidation indices in lupeol analogue (oxime) treated MCF-7 cells.…”