title: Heme oxygenase-1 inhibits rat and human breast cancer cell proliferation: mutual cross inhibition with indoleamine 2,3-dioxygenase.
abstract: Heme oxygenase-1 (HO-1) is the rate limiting enzyme of heme catabolism whereas indoleamine 2,3 dioxygenase (IDO) catabolizes tryptophan through the kynurenine pathway. We analyzed the expression and biological effects of these enzymes in rat and human breast cancer cell lines. We show that rat (NMU and 13762) but not human cells (MCF-7 and T47D) express HO-1. When overexpressed, we found this enzyme to have anti-proliferative and proapoptotic effects by antioxidant mechanisms in these four cell lines. We show that IDO is expressed by rat and human breast cancer cells. IDO inhibition with 1-MT and siRNA leads to diminished proliferation in rat cells. In contrast, HO-1 negative human cell lines increase proliferation upon IDO inhibition. Since we also demonstrate that IDO inhibits the anti-proliferative HO-1, we propose that IDO has opposite effects on proliferation depending on the coexpression or not of HO-1. We also describe that HO-1 inhibits IDO at the post-translational level through heme starvation. In vivo, we show that rat normal breast expresses HO-1 and IDO. In contrast, N-nitrosomethylurea-induced breast adenocarcinomas only express IDO. In conclusion, we show that HO-1/IDO cross-regulation modulates apoptosis and proliferation in rat and human breast cancer cells.
authors.affiliation: INSERM U 643, ITERT, 30 Bv. Jean Monnet, 44093, Nantes, cedex 1, France.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Hill
authors.forename: Victoria
authors.initials: V
authors.lastname: Pereira
authors.forename: Christine
authors.initials: C
authors.lastname: Chauveau
authors.forename: Rachid
authors.initials: R
authors.lastname: Zagani
authors.forename: Séverine
authors.initials: S
authors.lastname: Remy
authors.forename: Laurent
authors.initials: L
authors.lastname: Tesson
authors.forename: Daniel
authors.initials: D
authors.lastname: Mazal
authors.forename: Luis
authors.initials: L
authors.lastname: Ubillos
authors.forename: Régis
authors.initials: R
authors.lastname: Brion
authors.forename: Kashif
authors.initials: K
authors.lastname: Asghar
authors.forename: Kashif
authors.initials: K
authors.lastname: Ashgar
authors.forename: Mir Farzin
authors.initials: MF
authors.lastname: Mashreghi
authors.forename: Katja
authors.initials: K
authors.lastname: Kotsch
authors.forename: John
authors.initials: J
authors.lastname: Moffett
authors.forename: Cornelia
authors.initials: C
authors.lastname: Doebis
authors.forename: Martina
authors.initials: M
authors.lastname: Seifert
authors.forename: Jorge
authors.initials: J
authors.lastname: Boczkowski
authors.forename: Eduardo
authors.initials: E
authors.lastname: Osinaga
authors.forename: Ignacio
authors.initials: I
authors.lastname: Anegon
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006418:Heme / Q000737:chemistry; D051547:Heme Oxygenase-1 / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000494:pharmacology*; D016086:Lentivirus / Q000235:genetics; D015674:Mammary Neoplasms, Animal / Q000378:metabolism / Q000473:pathology*; D008770:Methylnitrosourea / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D034741:RNA, Small Interfering; D006418:Heme; D008770:Methylnitrosourea; D051547:Heme Oxygenase-1; D010100:Oxygen