title: CO-CBS-H2 S Axis: From Vascular Mediator to Cancer Regulator.
abstract: CO is a gaseous mediator generated by HO. Our previous studies revealed that CO generated from inducible HO-1 or from constitutive HO-2 modulates function of different heme proteins or enzymes through binding to their prosthetic ferrous heme to alter their structures, regulating biological function of cells and organs. Such CO-directed target macromolecules include sGC and CBS. In the liver, CO serves as a sinusoidal dilator through its action on sGC in hepatic stellate cells, while the same gas accounts for vasoconstrictor that inhibits H2S generated by CO-sensitive CBS in astrocytes. Since molecular O2 is a substrate for HO, the latter mechanism contributes to hypoxic vasodilation in neurovascular units. We have recently uncovered that stress-inducible CO in and around cancer cells suppresses CBS to result in decreased methylation of PFKFB3, the enzyme regulating PFK-1, leading to a shift of glucose biotransformation from glycolysis toward pentose phosphate pathway; such a metabolic remodeling causes chemoresistance through increasing NADPH and reduced glutathione under stress conditions for cancer cells. This article reviews the intriguing networks of CO-sensitive metabolic regulatory mechanisms in microcirculation and cancer.
authors.affiliation: Department of Biochemistry, Keio University School of Medicine, Japan Science and Technology Agency, ERATO Suematsu Gas Biology Project, Tokyo, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Suematsu
authors.affiliation: Department of Biochemistry, Keio University School of Medicine, Japan Science and Technology Agency, ERATO Suematsu Gas Biology Project, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Department of Biochemistry, Keio University School of Medicine, Japan Science and Technology Agency, ERATO Suematsu Gas Biology Project, Tokyo, Japan.
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Tokumoto
authors.affiliation: Department of Biochemistry, Keio University School of Medicine, Japan Science and Technology Agency, ERATO Suematsu Gas Biology Project, Tokyo, Japan.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Department of Biochemistry, Keio University School of Medicine, Japan Science and Technology Agency, ERATO Suematsu Gas Biology Project, Tokyo, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Kajimura
authors.affiliation: Department of Biochemistry, Keio University School of Medicine, Japan Science and Technology Agency, ERATO Suematsu Gas Biology Project, Tokyo, Japan.
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Kabe
mesh_terms: D000818:Animals; D002196:Capillaries / Q000378:metabolism / Q000473:pathology; D002248:Carbon Monoxide / Q000378:metabolism*; D003541:Cystathionine beta-Synthase / Q000378:metabolism*; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D006862:Hydrogen Sulfide / Q000378:metabolism*; D007728:Kupffer Cells / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000378:metabolism*; D009435:Synaptic Transmission
chemical_list: D009363:Neoplasm Proteins; D002248:Carbon Monoxide; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C105245:heme oxygenase-2; D003541:Cystathionine beta-Synthase; D006862:Hydrogen Sulfide
keywords: CO; cancer; chemoresistance; cystathionine β-synthase; glutathione; soluble guanylate cyclase