title: Ursolic acid simultaneously targets multiple signaling pathways to suppress proliferation and induce apoptosis in colon cancer cells.
abstract: Ursolic acid (UA), a natural pentacyclic triterpenoid carboxylic acid distributed in medical herbs, exerts antitumor effects and is emerging as a promising compound for cancer prevention and therapy, but its excise mechanisms of action in colon cancer cells remains largely unknown. Here, we identified the molecular mechanisms by which UA inhibited cell proliferation and induced apoptosis in human colon cancer SW480 and LoVo cells. Treatment with UA led to significant inhibitions in cell viability and clone formation and changes in cell morphology and spreading. UA also suppressed colon cancer cell migration by inhibiting MMP9 and upregulating CDH1 expression. Further studies showed that UA inhibited the phosphorylation of Akt and ERK proteins. Pretreatment with an Akt or ERK-specific inhibitor considerably abrogated the proliferation inhibition by UA. UA also significantly inhibited colon cancer cell COX-2 expression and PGE2 production. Pretreatment with a COX-2 inhibitor (celecoxib) abrogated the UA-induced cell proliferation. Moreover, we found that UA effectively promoted NF-κB and p300 translocation from cell nuclei to cytoplasm, and attenuated the p300-mediated acetylation of NF-κB and CREB2. Pretreatment with a p300 inhibitor (roscovitine) abrogated the UA-induced cell proliferation, which is reversed by p300 overexpression. Furthermore, UA treatment induced colon cancer cell apoptosis, increased the cleavage of PARP, caspase-3 and 9, and trigged the release of cytochrome c from mitochondrial inter-membrane space into cytosol. These results indicate that UA inhibits cell proliferation and induces apoptosis in colon cancer cells through simultaneous modulation of the multiple signaling pathways such as MMP9/CDH1, Akt/ERK, COX-2/PGE2, p300/NF-κB/CREB2, and cytochrome c/caspase pathways.
authors.affiliation: State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors.forename: Jingshu
authors.initials: J
authors.lastname: Wang
authors.forename: Liqun
authors.initials: L
authors.lastname: Liu
authors.forename: Huijuan
authors.initials: H
authors.lastname: Qiu
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
authors.forename: Wangbing
authors.initials: W
authors.lastname: Chen
authors.forename: Yun
authors.initials: Y
authors.lastname: Tian
authors.forename: Lingyi
authors.initials: L
authors.lastname: Fu
authors.forename: Dingbo
authors.initials: D
authors.lastname: Shi
authors.forename: Jianding
authors.initials: J
authors.lastname: Cheng
authors.forename: Wenlin
authors.initials: W
authors.lastname: Huang
authors.forename: Wuguo
authors.initials: W
authors.lastname: Deng
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000473:pathology*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D014315:Triterpenes / Q000494:pharmacology*; D000097245:Ursolic Acid
chemical_list: D000970:Antineoplastic Agents; D020169:Caspases; D051546:Cyclooxygenase 2; D045304:Cytochromes c; D015232:Dinoprostone; D050881:E1A-Associated p300 Protein; D016328:NF-kappa B; D014315:Triterpenes; D000097245:Ursolic Acid; C494360:EP300 protein, human