title: Inhibition of Wnt/β-catenin signaling mediates ursolic acid-induced apoptosis in PC-3 prostate cancer cells.
abstract: BACKGROUND
  Ursolic acid, a pentacyclic triterpenoid, is known to exert antitumor activity in breast, lung, liver and colon cancers. Nonetheless, the underlying mechanism of ursolic acid in prostate cancer cells still remains unclear. To investigate the antitumor mechanism, the apoptotic mechanism of ursolic acid via Wnt/β-catenin signaling was examined in PC-3 prostate cancer cells.
  
  
  METHODS
  Cytotoxicity assay, flow cytometry, immunofluorescence assay and western blotting were performed.
  
  
  RESULTS
  Ursolic acid showed cytotoxicity against PC-3, LNCaP and DU145 prostate cancer cells with IC50 of 35 μM, 47 μM and 80 μM, respectively. Also, ursolic acid significantly increased the number of ethidium homodimer stained cells and apoptotic bodies, and dose-dependently enhanced the sub-G1 apoptotic accumulation in PC-3 cells. Consistently, western blotting revealed that ursolic acid effectively cleaved poly (ADP-ribose) polymerase (PARP), activated caspase-9 and -3, suppressed the expression of survival proteins such as Bcl-XL, Bcl-2 and Mcl-1, and upregulated the expression of Bax in PC-3 cells. Interestingly, ursolic acid suppressed the expression of Wnt5α/β and β-catenin, and enhanced the phosphorylation of glycogen synthase kinase 3 β (GSK3β). Furthermore, the GSK3β inhibitor SB216763 or Wnt3a-conditioned medium (Wnt3a-CM) reversed the cleavages of caspase-3 and PARP induced by ursolic acid in PC-3 cells.
  
  
  CONCLUSIONS
  Our findings suggest that ursolic acid induces apoptosis via inhibition of the Wnt5/β-catenin pathway and activation of caspase in PC-3 prostate cancer cells. These results support scientific evidence that medicinal plants containing ursolic acid can be applied to cancer prevention and treatment as a complement and alternative medicine (CAM) agent.
authors.affiliation: College of Oriental Medicine, Kyung Hee University, Seoul 130-701, South Korea. sungkim7@khu.ac.kr.
authors.forename: Ji-Hyuk
authors.initials: JH
authors.lastname: Park
authors.forename: Hee-Young
authors.initials: HY
authors.lastname: Kwon
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Sohn
authors.forename: Kyung A
authors.initials: KA
authors.lastname: Kim
authors.forename: Bonglee
authors.initials: B
authors.lastname: Kim
authors.forename: Soo-Jin
authors.initials: SJ
authors.lastname: Jeong
authors.forename: Jun Ho
authors.initials: JH
authors.lastname: Song
authors.forename: Jin Suk
authors.initials: JS
authors.lastname: Koo
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Kim
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D057809:HEK293 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology*; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D000071818:Wnt-5a Protein; D060509:Wnt3A Protein / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*; D000097245:Ursolic Acid
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D017077:Culture Media, Conditioned; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D014315:Triterpenes; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D060509:Wnt3A Protein; D051176:beta Catenin; D000097245:Ursolic Acid; C495270:CTNNB1 protein, human; C555510:WNT3A protein, human; C085389:WNT5A protein, human; C435831:WNT5B protein, human; C000605506:GSK3B protein, human