Nitric oxide inactivates the retinoblastoma pathway in chronic inflammation.
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.
Ying
Lei
L
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, School of Medicine, University of South Carolina, Columbia, South Carolina 29208, USA.
Hofseth
Anne B
AB
Browning
Darren D
DD
Nagarkatti
Mitzi
M
Nagarkatti
Prakash S
PS
Hofseth
Lorne J
LJ
D000818:Animals; D003092:Colitis / Q000150:complications / Q000201:enzymology / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000201:enzymology / Q000209:etiology / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism; D050687:E2F1 Transcription Factor / Q000378:metabolism; D006162:Guanylate Cyclase / Q000378:metabolism; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism*; D013096:Spermine / Q000031:analogs & derivatives / Q000494:pharmacology
D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D020030:Nitric Oxide Donors; D016160:Retinoblastoma Protein; C091861:spermine nitric oxide complex; D013096:Spermine; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020930:MAP Kinase Kinase Kinases; D006162:Guanylate Cyclase; D006152:Cyclic GMP