Embelin-Induced Apoptosis of Human Prostate Cancer Cells Is Mediated through Modulation of Akt and β-Catenin Signaling

• Published in: PloS one Vol. 10; no. 8; p. e0134760
• Main Authors: Park, Nahee, Baek, Hyoung Seok, Chun, Young-Jin
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 07.08.2015; Public Library of Science (PLoS)
• Subjects: Activation; AKT protein; Apoptosis; Apoptosis - drug effects; Apoptosis-inducing factor; Attenuation; Bcl-2 protein; Bcl-x protein; Benzoquinones - pharmacology; beta Catenin - metabolism; Breast cancer; c-Myc protein; Cancer; Cell culture; Cell Line, Tumor; Cell migration; Cell Movement - drug effects; Cell Proliferation - drug effects; Choriocarcinoma; Cyclin D1; Cyclooxygenase 2 - metabolism; Cyclooxygenase-2; Cytochrome; Cytochrome c; Down-Regulation - drug effects; Enzyme Activation - drug effects; Epithelial cells; Gene expression; Glycogen; Glycogen synthase kinase 3; Glycogen Synthase Kinase 3 - antagonists & inhibitors; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; Hepatoma; Humans; Immunoglobulins; Induced voltage; Kinases; Lithium; Lithium chloride; Liver cancer; Male; Matrix metalloproteinase; Membrane potential; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Neoplasm Invasiveness; Oligomerization; Pancreatic cancer; Penicillin; Pharmacy; Phosphorylation; Prostate cancer; Prostatic Neoplasms - enzymology; Prostatic Neoplasms - pathology; Protein Kinase Inhibitors - pharmacology; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Rodents; Signal Transduction - drug effects; Signaling; Time dependence; Time Factors; Transcription; Translocation; Tumor cell lines
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0134760

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.