Suppression of Wnt/β-catenin signaling inhibits prostate cancer cell proliferation

Abstract

Although mounting evidence has demonstrated an important role of Wnt/β-catenin signaling in the development and progression of cancer, the therapeutic potential of small molecules that target this pathway for prostate cancer remains largely unknown. We reported herein that the highly invasive androgen-independent PC-3 and DU145 human prostate cancer cells exhibited higher levels of Wnt/ β-catenin signaling than the androgen-dependent LNCaP prostate cancer cells and non-cancerous PZ-HPV-7 and PWR-1E prostate cells, and that exogenous Wnt3A treatment exaggerated the difference of the Wnt/β-catenin signaling levels among these prostate cells. Furthermore, we demonstrated that the non-steroidal anti-inflammatory drug, sulindac sulfide, the cyclooxygenase-2 (COX-2) selective inhibitor, celecoxib, and the nitric oxide-donating aspirin derivative, NO-ASA, blocked Wnt/β-catenin signaling in PC-3 and DU145 cells. These effects occurred at concentrations comparable to those required to inhibit cell proliferation, indicating that the inhibitory effect of these drugs on prostate cancer cell proliferation may involve the suppression of Wnt/β-catenin signaling. Finally, we showed that a novel small molecule inhibitor of Wnt/β-catenin signaling, PKF118-310, inhibited Wnt/β-catenin signaling and proliferation in prostate cancer cells within the same concentration range. Together, these results suggest that small molecules that inhibit Wnt/β-catenin signaling have therapeutic potential for the prevention or treatment of prostate cancer.

Anti-proliferative potential of curcumin in androgen-dependent prostate cancer cells occurs through modulation of the Wingless signaling pathway

“…4). Such an arrest in G2/M and concomitant decrease in cyclin B1 expression or decrease in PCNA expression were also observed in HCT-116 colon cancer cells (17), in BxPC-3 human pancreatic cancer cells (44), in human breast cancer cells (14,45) and in human bladder cancer T24 cells (46) This decrease of 22rv1 cell proliferation suggests that curcumin could exhibit an effect on the Wnt signaling pathway as it was reported that the suppression of this Wnt pathway inhibits prostate cancer cell proliferation (11). We then assessed the effectiveness of curcumin on prostate cancer cell proliferation and especially on the Wnt pathway.…”

“…Many natural compounds were reported to exhibit their chemopreventive potential through the modulation of the canonical Wnt signaling pathway in several cancer cell types (7)(8)(9)(10)(11). Curcumin (diferuloylmethane), from the roots of Curcuma longa and well characterized for its anti-carcinogenic, anti-proliferative, anti-inflammatory, anti-angiogenic and anti-oxidant properties (12,13) was also shown to affect the Wnt signaling especially in colon, gastric, intestinal and breast cancer cells (14)(15)(16)(17).…”

Endothelial NO Synthase-Dependent S-Nitrosylation of β-Catenin Prevents Its Association with TCF4 and Inhibits Proliferation of Endothelial Cells Stimulated by Wnt3a

“…Thus, the two functions of ␤-catenin are regulated by SNO of different residues, Cys466 and Cys619. Previous studies have shown that NO donors, including NO-donating aspirin or other NO-releasing chemical entities, could repress the transcriptional activity of ␤-catenin, and some have suggested that SNO of ␤-catenin could be responsible for this effect (29)(30)(31)(39)(40)(41). Chemical NO-donating agents have shown promise on cancer cells, where they attenuate Wnt/␤-catenin signaling, reduce proliferation, and induce apoptosis (30,31).…”

Downregulation of Dickkopf-1 is responsible for high proliferation of breast cancer cells via losing control of Wnt/β-catenin signaling

“…Next, we try to identify the downstream effectors of DKK-1 in promotion of proliferation of breast cancer cells. A hallmark of canonical Wnt pathway activation which can enhance proliferation ability of several tumor cell lines shows an increase in β-catenin-dependent transcription, primarily as a result of β-catenin protein stabilization [9,10,31,32] . Thus, we assessed the effects of DKK-1 on the phosphorylation of β-catenin which led to β-catenin degradation.…”

“…Recent studies show that the signal transduction pathways, such as NOTCH3-mediated signaling, ErbB-mediated cascade, serum and glucocorticoid-inducible kinase (SGK)-mediated signaling, G proteincoupled receptor GPR40-mediated signaling and ERK/MAPK signaling, are involved in the regulation of breast cancer cell proliferation [6][7][8] . It has been reported that Wnt signaling plays an important role in regulation of cell proliferation in several cancers, such as prostate cancer, lung cancer, myeloma and www.chinaphar.com Zhou XL et al Acta Pharmacologica Sinica npg colon cancer [9][10][11][12] .…”