Abstract
There is increasing evidence that embelin, an active component of Embelia ribes, induces apoptosis in human cancer cells, but the detailed mechanisms are still unclear. Here, we have investigated the effect of embelin on the growth of human prostate cancer cells. Embelin strongly inhibited cell growth especially in human prostate cancer cell lines, including PC3, DU145, LNCaP-LN3 and normal prostate epithelial cell, RWPE-1 compared to breast cancer (MDA-MB-231, MCF-7, and T47D), hepatoma (HepG2, Hep3B, and HuH-7), or choriocarcinoma (JEG-3). We observed that embelin induced apoptosis of PC3 cells in a time-dependent manner correlated with decreased expression of Bcl-2, Bcl-xL, and Mcl-1, increased translocation of Bax into mitochondria, and a reduction in the mitochondrial membrane potential. Furthermore, embelin induced voltage-dependent anion channel (VDAC) 1 expression and oligomerization, which may promote cytochrome c and AIF release. Because embelin was able to inhibit Akt activation and cyclooxygenase-2 expression, the effects on Wnt/ β-catenin signaling were determined. Embelin activated glycogen synthase kinase (GSK)-3β by preventing phosphorylation and suppressed β-catenin expression. Attenuation of β-catenin-mediated TCF transcriptional activity and gene transcription, such as cyclin D1, c-myc, and matrix metalloproteinase (MMP)-7, were shown in embelin-treated cells. The changes in β-catenin levels in response to embelin were blocked by lithium chloride, a GSK-3 inhibitor, indicating that embelin may decrease β-catenin expression via GSK-3β activation. Furthermore, exposure of PC3 cells to embelin resulted in a significant decrease in cell migration and invasion. In conclusion, these findings suggest that inhibition of Akt signaling and activation of GSK-3β partially contributes to the pro-apoptotic effect of embelin in prostate cancer cells.
Highlights
Embelin (2, 5-dihydroxy-3-undecyl-1, 4- benzoquinone), isolated as the active component of the fruit of the Embelia ribes Burm (Myrsinaceae), has been used to treat fever and shown to have anti-inflammatory, anti-carcinogenic [1], anti-oxidant [2], anti-convulsant [3], and anti-PLOS ONE | DOI:10.1371/journal.pone.0134760 August 7, 2015Embelin-Induced Apoptosis through Akt and β-Catenin Modulation bacterial activities [4,5]
Cell viability was decreased by embelin in human prostate cancer cell lines and prostate epithelial cell including PC3, DU145, LNCaP-LN3 and RWPE-1 with IC50 values of 23.6 μM, 11.0 μM, 32.0 μM, and over 200 μM respectively when cells were cultured for 24 h (Fig 1E)
Because the mitochondrial permeability transition may lead to apoptosis, we determined the effect of embelin on mitochondrial membrane potential (Δψm)
Summary
Embelin (2, 5-dihydroxy-3-undecyl-1, 4- benzoquinone), isolated as the active component of the fruit of the Embelia ribes Burm (Myrsinaceae), has been used to treat fever and shown to have anti-inflammatory, anti-carcinogenic [1], anti-oxidant [2], anti-convulsant [3], and anti-PLOS ONE | DOI:10.1371/journal.pone.0134760 August 7, 2015Embelin-Induced Apoptosis through Akt and β-Catenin Modulation bacterial activities [4,5]. Embelin is known to suppress cell proliferation and induce apoptosis in many human cancer cells, the molecular mechanisms of these effects remain unclear. Initiation signals for the intrinsic pathway are generated by developmental cues or cellular damage that causes the loss of mitochondrial membrane potential and the release of proapoptotic proteins [9, 10]. Akt regulates cellular signaling networks that are involved in processes linked to the cellular proliferation, differentiation, and metabolism and activates a COX-2-mediated anti-apoptotic pathway that involves Mcl-1 [18,19]. The present study shows that embelin induces mitochondrial-dependent apoptosis and suppression of β-catenin expression via Akt inhibition and GSK-3β activation in human prostate cancer cells
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