title: Upregulation of heat shock protein 27 confers resistance to actinomycin D-induced apoptosis in cancer cells.
abstract: Actinomycin D (Act D) is a general transcriptional inhibitor that is approved for the treatment of sarcomas, and Wilms, germ cell and trophoblastic tumors. Little is known about the molecular mechanisms that dictate the sensitivity of cancer cells to Act D. In this study, we investigated the effects of Act D on heat shock proteins (HSPs) and the expression and roles of HSP27 in Act D-induced cancer cell apoptosis. We show that Act D upregulates HSP27 and HSP70 expression in cancer cells, whereas it inhibits HSP90 expression. The upregulation of HSP27 by Act D is not attributable to changes in HSP27 transcription or HSP27 synthesis. HSP27 knockdown leads to an increase in Act D-induced caspase 3 and caspase 7 cleavage, and sensitizes rhabdosarcoma cells and breast cancer cells to Act D-induced apoptosis. We conclude that upregulation of HSP27 represents an adaptive response that compromises the anticancer activity of Act D.
authors.affiliation: State Key Laboratory of Biotherapy, Section of Signal Transduction and Molecular Targeted Therapy, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Ma
authors.forename: Yan
authors.initials: Y
authors.lastname: Teng
authors.forename: Hui
authors.initials: H
authors.lastname: Hua
authors.forename: Jinlin
authors.initials: J
authors.lastname: Hou
authors.forename: Ting
authors.initials: T
authors.lastname: Luo
authors.forename: Yangfu
authors.initials: Y
authors.lastname: Jiang
mesh_terms: D000222:Adaptation, Physiological; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053179:Caspase 7 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D003609:Dactinomycin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D055551:HSP27 Heat-Shock Proteins / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D006360:Heat-Shock Proteins; D006801:Humans; D018832:Molecular Chaperones; D059748:Proteolysis; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction
chemical_list: D000903:Antibiotics, Antineoplastic; D055551:HSP27 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D034741:RNA, Small Interfering; D003609:Dactinomycin; D053148:Caspase 3; D053179:Caspase 7
keywords: actinomycin D; apoptosis; cancer; heat shock protein