title: Induction of apoptosis and stress response in ovarian carcinoma cell lines treated with ST1926, an atypical retinoid.
abstract: To understand the molecular mechanisms mediating apoptosis induction by a novel atypical retinoid, ST1926, the cellular response to drug treatment was investigated in IGROV-1 ovarian carcinoma cells carrying wild-type p53 and a cisplatin-resistant p53 mutant subline (IGROV-1/Pt1). Despite a similar extent of drug-induced DNA strand breaks, the level of apoptosis was substantially higher in p53 wild-type cells. p53 activation and early upregulation of p53-target genes were consistent with p53-dependent apoptosis in IGROV-1 cells. Stress-activated protein kinases were activated in both cell lines in response to ST1926. This event and activation of AP-1 were more pronounced in IGROV-1/Pt1 cells, in which the modulation of DNA repair-associated genes suggests an increased ability to repair DNA damage. Inhibition of JNK or p38 stimulated ST1926-induced apoptosis only in IGROV-1 cells, whereas inhibition of ERKs enhanced apoptosis in both the cell lines. Such a pattern of cellular response and modulation of genes implicated in DNA damage response supports that the genotoxic stress is a critical event mediating drug-induced apoptosis. The results are consistent with apoptosis induction through p53-dependent and -independent pathways, regulated by MAP kinases, which likely play a protective role.
authors.affiliation: Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Zuco
authors.forename: C
authors.initials: C
authors.lastname: Zanchi
authors.forename: G
authors.initials: G
authors.lastname: Cassinelli
authors.forename: C
authors.initials: C
authors.lastname: Lanzi
authors.forename: R
authors.initials: R
authors.lastname: Supino
authors.forename: C
authors.initials: C
authors.lastname: Pisano
authors.forename: R
authors.initials: R
authors.lastname: Zanier
authors.forename: V
authors.initials: V
authors.lastname: Giordano
authors.forename: E
authors.initials: E
authors.lastname: Garattini
authors.forename: F
authors.initials: F
authors.lastname: Zunino
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000633:toxicity; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002277:Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002934:Cinnamates / Q000494:pharmacology* / Q000633:toxicity; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000032:analysis / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D013312:Stress, Physiological; D018808:Transcription Factor AP-1 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C472791:3-(4'-hydroxy-3'-adamantylbiphenyl-4-yl)acrylic acid; D000970:Antineoplastic Agents; D002934:Cinnamates; D004273:DNA, Neoplasm; D018809:Proliferating Cell Nuclear Antigen; D018808:Transcription Factor AP-1; D016159:Tumor Suppressor Protein p53; D020928:Mitogen-Activated Protein Kinases; D020169:Caspases; D000218:Adamantane