title: Sulforaphane induces cytotoxicity and lysosome- and mitochondria-dependent cell death in colon cancer cells with deleted p53.
abstract: Mechanisms and pathways responsible for cytotoxicity of sulforaphane (SF) in colon cancer cells with deleted p53 were investigated during 48 h of exposure. SF showed dose-dependent cytotoxicity and proapoptotic activity in the present model. In addition, in HCT-116 p53KO cells SF induced DNA damage with the subsequent cellular response and signaling not including p53 and caspase-2 pathways. Conversely, in SF-treated cells JNK was activated which led to an early lysosomal membrane permeabilization, release of cathepsin B and D and activation of Bid by specific cleavage. Concomitantly, the expression of Bax increased in the presence of JNK-mediated Bcl-2 inhibition which was followed by mitochondrial release of cytochrome c and activation of apoptosis. These results suggest that SF may be useful as a chemopreventive agent in colon cancer with inactivated or lost p53.
authors.affiliation: Department of Medical Biology and Genetics, Charles University in Prague, Faculty of Medicine in Hradec Kralove, Simkova 870, 500 38 Hradec Kralove, Czech Republic. rudolf@lfhk.cuni.cz
authors.forename: Emil
authors.initials: E
authors.lastname: Rudolf
authors.forename: Miroslav
authors.initials: M
authors.lastname: Cervinka
mesh_terms: D016588:Anticarcinogenic Agents / Q000633:toxicity*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D004249:DNA Damage / Q000187:drug effects; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017879:Isothiocyanates; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D013312:Stress, Physiological / Q000187:drug effects; D013454:Sulfoxides; D013861:Thiocyanates / Q000633:toxicity*; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D016588:Anticarcinogenic Agents; C494826:BAX protein, human; D006360:Heat-Shock Proteins; D017879:Isothiocyanates; D013454:Sulfoxides; D013861:Thiocyanates; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D048670:MAP Kinase Kinase 4; C016766:sulforaphane