title: Ursolic acid induces apoptosis through mitochondrial intrinsic pathway and suppression of ERK1/2 MAPK in HeLa cells.
abstract: Ursolic acid (UA), a natural pentacyclic triterpenoid compound, has been demonstrated to induce apoptosis in various tumors. The aim of the present study was to elucidate the molecular mechanisms of UA-induced apoptosis in HeLa cells. Here, we reported that UA induced apoptosis through the mitochondrial intrinsic pathway in HeLa cells, as shown by release of cytosol cytochrome c, activation of caspase-9 and -3, reduction of Bcl-2 and Bcl-xL, and increase of Bax and Bak. UA down-regulated the phosphorylation of ERK1/2 and p38, whereas phosphorylation of JNK was unchanged. The roles of ERK1/2 and p38 were further confirmed using the ERK1/2 inhibitor (U0126) and p38 inhibitor (SB203580). U0126 markedly increased UA-induced the Bax/Bcl-2 ratio, the increase of cytosol cytochrome c, and the levels of cleaved caspase-3, but SB203580 had little effects on the above characters, suggesting the ERK1/2 signaling pathway is required for apoptosis. Furthermore, UA up-regulated DUSP 1, 2, 4, 5, 6, 7, 9, and 10 mRNA expressions, which may be a clue for the role of dephosphorylation of ERK1/2 and p38. These data suggested that the apoptotic mechanism of UA treatment in HeLa cells was through the mitochondrial intrinsic pathway and closely associated with the suppression of the ERK1/2 signaling pathway.
authors.affiliation: Key Laboratory of Chemistry of Plant Resources in Arid Regions, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, China.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Li
authors.forename: Xueying
authors.initials: X
authors.lastname: Lu
authors.forename: Hongxue
authors.initials: H
authors.lastname: Qi
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Li
authors.forename: Xiangwen
authors.initials: X
authors.lastname: Xiao
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Gao
mesh_terms: D000972:Antineoplastic Agents, Phytogenic; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D054637:Dual-Specificity Phosphatases / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008928:Mitochondria / Q000235:genetics* / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics* / Q000502:physiology*; D014315:Triterpenes / Q000494:pharmacology*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000097245:Ursolic Acid
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D053148:Caspase 3; D053453:Caspase 9; D045304:Cytochromes c; D054637:Dual-Specificity Phosphatases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D019253:Proto-Oncogene Proteins c-bcl-2; D014315:Triterpenes; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D048051:p38 Mitogen-Activated Protein Kinases; D000097245:Ursolic Acid; C494772:BAK1 protein, human; C494826:BAX protein, human; C494811:BCL2L1 protein, human; C535150:MAPK1 protein, human