title: Cyclic 3',5'-guanosine monophosphate-dependent protein kinase inhibits colon cancer cell adaptation to hypoxia.
abstract: BACKGROUND
  Type 1 cyclic 3',5'-guanosine monophosphate-dependent protein kinase (PKG) has recently been reported to inhibit tumor growth and angiogenesis. These effects suggest that PKG activation may have therapeutic value for colon cancer treatment, but the signaling downstream of this enzyme is poorly understood. The present study examined the mechanism underlying the inhibition of angiogenesis by PKG.
  
  
  METHODS
  The effect of ectopically expressed PKG on colon cancer cell adaptation to a 1% O(2) (hypoxic) environment was examined in vitro by measuring hypoxic markers, cell death/viability, and hypoxia inducible factor (HIF) activity.
  
  
  RESULTS
  Ectopic PKG inhibited angiogenesis in SW620 xenografts and significantly attenuated hypoxia-induced increases in vascular endothelial growth factor at both the mRNA and protein levels. PKG activation also blocked hypoxia-induced hexokinase 2 expression, which corresponded with reduced cellular adenosine triphosphate levels. Moreover, PKG expression significantly reduced cell viability and promoted necrotic cell death after 2 days in a hypoxic environment. To gain some mechanistic insight, the effect of PKG on HIF activation was determined using luciferase reporter assays. PKG activation inhibited HIF transcriptional activity in several colon cancer cell lines, including SW620, HCT116, and HT29. The mechanism by which PKG can inhibit HIF activity is not known, but it does not affect HIF-1α protein accumulation or nuclear translocation.
  
  
  CONCLUSIONS
  These findings demonstrate for the first time that PKG can block the adaptation of colon cancer cells to hypoxia and highlights this enzyme for further evaluation as a potential target for colon cancer treatment.
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, Georgia, USA.
authors.forename: In-Kiu
authors.initials: IK
authors.lastname: Kwon
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.forename: Nikhil
authors.initials: N
authors.lastname: Prakash
authors.forename: Renee
authors.initials: R
authors.lastname: Bozard
authors.forename: Troy A
authors.initials: TA
authors.lastname: Baudino
authors.forename: Kebin
authors.initials: K
authors.lastname: Liu
authors.forename: Muthusamy
authors.initials: M
authors.lastname: Thangaraju
authors.forename: Zheng
authors.initials: Z
authors.lastname: Dong
authors.forename: Darren D
authors.initials: DD
authors.lastname: Browning
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000502:physiology*; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000502:physiology; D051379:Mice; D009336:Necrosis; D009389:Neovascularization, Pathologic / Q000517:prevention & control*
chemical_list: D051793:Hypoxia-Inducible Factor 1; D017869:Cyclic GMP-Dependent Protein Kinases