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Nitric Oxide Inactivates the Retinoblastoma Pathway in Chronic Inflammation

¹ Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy; ² Department of Pathology, School of Medicine, University of South Carolina, Columbia, South Carolina; and ³ Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, Georgia

Requests for reprints: Lorne J. Hofseth, Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of South Carolina, Coker Life Sciences, Room 513C, 770 Sumter Street, Columbia, SC 29208. Phone: 803-777-6627; Fax: 803-777-8356; E-mail: hofseth{at}cop.sc.edu.

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. [Cancer Res 2007;67(19):9286–93]

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