title: The induction of heme oxygenase-1 suppresses heat shock protein 90 and the proliferation of human breast cancer cells through its byproduct carbon monoxide.
abstract: Heme oxygenase (HO)-1 is an oxidative stress-response enzyme which catalyzes the degradation of heme into bilirubin, ferric ion, and carbon monoxide (CO). Induction of HO-1 was reported to have antitumor activity; the inhibitory mechanism, however, is still unclear. In the present study, we found that treatment with [Ru(CO)3Cl2]2 (RuCO), a CO-releasing compound, reduced the growth of human MCF7 and MDA-MB-231 breast cancer cells. Analysis of growth-related proteins showed that treatment with RuCO down-regulated cyclinD1, CDK4, and hTERT protein expressions. Interestingly, RuCO treatment resulted in opposite effects on wild-type and mutant p53 proteins. These results were similar to those of cells treated with geldanamycin (a heat shock protein (HSP)90 inhibitor), suggesting that RuCO might affect HSP90 activity. Moreover, RuCO induced mutant p53 protein destabilization accompanied by promotion of ubiquitination and proteasome degradation. The induction of HO-1 by cobalt protoporphyrin IX (CoPP) showed consistent results, while the addition of tin protoporphyrin IX (SnPP), an HO-1 enzymatic inhibitor, diminished the RuCO-mediated effect. RuCO induction of HO-1 expression was reduced by a p38 mitogen-activated protein kinase inhibitor (SB203580). Additionally, treatment with a chemopreventive compound, curcumin, induced HO-1 expression accompanied with reduction of HSP90 client protein expression. The induction of HO-1 by curcumin inhibited 12-O-tetradecanoyl-13-acetate (TPA)-elicited matrix metalloproteinase-9 expression and tumor invasion. In conclusion, we provide novel evidence underlying HO-1's antitumor mechanism. CO, a byproduct of HO-1, suppresses HSP90 protein activity, and the induction of HO-1 may possess potential as a cancer therapeutic.
authors.affiliation: Department of Pathology, Chi-Mei Hospital, Tainan, Taiwan; Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Wen-Ying
authors.initials: WY
authors.lastname: Lee
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yen-Chou
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Biochemistry, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chwen-Ming
authors.initials: CM
authors.lastname: Shih
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Biochemistry, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chun-Mao
authors.initials: CM
authors.lastname: Lin
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Biochemistry, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chia-Hsiung
authors.initials: CH
authors.lastname: Cheng
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Biochemistry, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Ku-Chung
authors.initials: KC
authors.lastname: Chen
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Biochemistry, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. Electronic address: cwlin@tmu.edu.tw.
authors.forename: Cheng-Wei
authors.initials: CW
authors.lastname: Lin
mesh_terms: D016227:Benzoquinones / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002248:Carbon Monoxide / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003474:Curcumin / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects / Q000502:physiology; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D051547:Heme Oxygenase-1 / Q000096:biosynthesis*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D061986:MCF-7 Cells
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D002248:Carbon Monoxide; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D003474:Curcumin; C001277:geldanamycin
keywords: 12-O-tetradecanoylphorbol-13-acetate; 17-AAG; 17-allylamino-17-demethoxygeldanamycin; 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide; CDK; CHX; CO; Carbon monoxide; CoPP; FePP; GA; HO-1; HSP90; Heat shock protein 90; Heme oxygenase-1; LDH; MAPK; MTT; SnPP; TPA; carbon monoxide; cobalt protoporphyrin IX; cyclin dependent kinase; cycloheximide; ferric protoporphyrin IX; geldanamycin; heat shock protein 90; heme oxygenase-1; lactate dehydrogenase; mitogen-activated protein kinase; p53; tin protoporphyrin IX