BUBR1 Insufficiency Is Correlated with eNOS Reduction Experimentally In Vitro and In Vivo, and in Gastric Cancer Tissue

Anticancer Res. 2018 Nov;38(11):6099-6106. doi: 10.21873/anticanres.12960.

Abstract

Background/aim: Budding uninhibited by benzimidazole-related 1 (BUBR1) and endothelial nitric oxide synthase (eNOS) are related to aging and angiogenesis. This study examined the effect of low BUBR1 expression on eNOS expression in vivo, in vitro, and human gastric cancer tissues.

Materials and methods: Human umbilical vein endothelial cells (HUVECs) were passaged to investigate the effect of aging on BUBR1 and eNOS expression; expression of eNOS and phospho-eNOS protein was assessed in BUBR1 siRNA-transfected HUVECs. Additionally, guanosine 3',5' cyclic monophosphate (cGMP) and eNOS protein levels were measured in BUBR1-insufficient mice (Bubr1L/-). BUBR1 and eNOS expression levels were also evaluated in human gastric cancer tissues.

Results: BUBR1 and eNOS, but not p-eNOS, levels were reduced significantly in aged and BUBR1 siRNA-transfected HUVECs. Additionally, cGMP production and the eNOS protein level were reduced in Bubr1L/- mice. Human gastric cancer tissues with low BUBR1 expression showed no eNOS expression.

Conclusion: A decrease in BUBR1 reduced eNOS bioavailability through a pathway other than eNOS phosphorylation.

Keywords: BUBR1; aging; angiogenesis; eNOS.

MeSH terms

  • Age Factors
  • Animals
  • Cell Cycle Proteins / deficiency
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cellular Senescence / physiology
  • Cyclic GMP / biosynthesis
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Immunohistochemistry
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nitric Oxide Synthase Type III / biosynthesis*
  • Nitric Oxide Synthase Type III / metabolism
  • Phosphorylation
  • Protein Serine-Threonine Kinases / deficiency*
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • RNA, Small Interfering / genetics
  • Stomach Neoplasms / enzymology*
  • Transfection
  • Vascular Endothelial Growth Factor A / pharmacology

Substances

  • Bub1b protein, mouse
  • Cell Cycle Proteins
  • RNA, Small Interfering
  • Vascular Endothelial Growth Factor A
  • NOS3 protein, human
  • Nitric Oxide Synthase Type III
  • Nos3 protein, mouse
  • BUB1 protein, human
  • Protein Serine-Threonine Kinases
  • Cyclic GMP