CO-CBS-H2S Axis: From Vascular Mediator to Cancer Regulator

Makoto Suematsu, Takashi Nakamura, Yasuhito Tokumoto, Takehiro Yamamoto, Mayumi Kajimura, Yasuaki Kabe

Research output: Contribution to journalReview articlepeer-review

17 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)183-190
Number of pages8
Issue number3
Publication statusPublished - 2016


  • CO
  • cancer
  • chemoresistance
  • cystathionine β-synthase
  • glutathione
  • soluble guanylate cyclase

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


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