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PMID: 17909036 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Nitric oxide inactivates the retinoblastoma pathway in chronic inflammation.

Cancer research ·Vol. 67 ·No. 19 ·2007-10-01 ·Pages 9286-93

Ying L, Hofseth AB, Browning DD, Nagarkatti M, Nagarkatti PS, Hofseth LJ

Abstract

Patients with chronic inflammatory bowel disease have a high risk of colon cancer. The molecules that initiate and promote colon cancer and the cancer pathways altered remain undefined. Here, using in vitro models and a mouse model of colitis, we show that nitric oxide (NO) species induce retinoblastoma protein (pRb) hyperphosphorylation and inactivation, resulting in increased proliferation through the pRb-E2F1 pathway. NO-driven pRb hyperphosphorylation occurs through soluble guanylyl cyclase/guanosine 3',5'-cyclic monophosphate signaling and is dependent on the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase MEK/ERK and phosphatidylinositol 3-kinase/AKT pathways. Our results reveal a link between NO and pRb inactivation and provide insight into molecules that can be targeted in the prevention of the inflammation-to-cancer sequence.

MeSH Terms
Animals Colitis/complications,enzymology,metabolism Colonic Neoplasms/enzymology,etiology,metabolism Cyclic GMP/metabolism E2F1 Transcription Factor/metabolism Guanylate Cyclase/metabolism HCT116 Cells HT29 Cells Humans MAP Kinase Kinase Kinases/metabolism Mice Mice, Inbred C57BL Nitric Oxide/metabolism,pharmacology Nitric Oxide Donors/pharmacology Nitric Oxide Synthase Type II/deficiency,metabolism Phosphatidylinositol 3-Kinases/metabolism Phosphorylation Proto-Oncogene Proteins c-akt/metabolism Retinoblastoma Protein/metabolism Spermine/analogs & derivatives,pharmacology
Chemicals
E2F1 Transcription Factor E2f1 protein, mouse Nitric Oxide Donors Retinoblastoma Protein spermine nitric oxide complex Spermine Nitric Oxide Nitric Oxide Synthase Type II Nos2 protein, mouse Phosphatidylinositol 3-Kinases Proto-Oncogene Proteins c-akt MAP Kinase Kinase Kinases Guanylate Cyclase Cyclic GMP
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Ying Lei
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, School of Medicine, University of South Carolina, Columbia, South Carolina 29208, USA.
Hofseth Anne B
Browning Darren D
Nagarkatti Mitzi
Nagarkatti Prakash S
Hofseth Lorne J
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Article Info
Journal
Cancer research
Abbr.
Cancer Res
ISSN
0008-5472
DOI
10.1158/0008-5472.CAN-07-2238
Published
2007-10-01
Pages
9286-93
Language
English
Region
United States
NLM ID
2984705R
PMCID
PMC2752153
Subset
IM
Grants
NCCIH NIH HHS · P01 AT003961 · United States
NCCIH NIH HHS · P01 AT003961-01A1 · United States
NCRR NIH HHS · P20 RR017698 · United States
NCRR NIH HHS · P20 RR017698-057289 · United States
External Links
PubMed source DOI: 10.1158/0008-5472.CAN-07-2238 PMC Full Text View journal details
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