Our Science – Ridnour Website
Lisa Ann Ridnour, Ph.D.
Dr. Ridnour joined the research group of Dr. David Wink (NCI) in 2003. Her research interests include nitric oxide (NO) regulation of extracellular matrix during cancer progression. In collaboration with Dr. David Roberts (NCI), a novel biphasic crosstalk relationship between NO and the angiogenesis inhibitor thrombospondin-1 (TSP-1) was discovered. NO modulates matrix metalloproteinase (MMP-9)/tissue inhibitor of metalloproteinase (TIMP-1) ratios in immune and tumor cells. Alteration of MMP/TIMP balance occurs during wound response, tumor progression and metastasis. While TIMP-1 is a potent inhibitor of MMP-9, both predict poor survival in cancer patients. In collaboration with Dr. Stefan Ambs (NCI), correlations between NOS2 and both TIMP-1 and MMP-9 in human breast tumors were discovered. TIMP-1 nitration at two key tyrosine residues that are critical for TIMP-1 inhibition of active MMP-9 enzyme was identified. This nitration event occurred at NO concentrations that increase both MMP-9 secretion and TIMP-1 binding to its receptor CD63, which promotes survival through CD63/PI3k/Akt/BAD signaling. These observations offer a novel mechanism deciphering how both MMP-9 and TIMP-1 can predict poor cancer patient survival, which may involve at least in part NO-mediated TIMP-1 nitration that redirects its function away from MMP-9 inhibition and toward TIMP-1/CD63 pro-survival signaling. In collaboration with Dr. Carol Colton at Duke University, a protective role for NO regulation of MMP-9/TIMP-1 balance increased plaque clearance in Alzheimerâ€™s disease and this was associated with reduced TIMP-1 expression and increased MMP-9 activity. Together, this work demonstrates a role for NO in the regulation of matrix reorganization in inflammatory disease.
1. Church SL, Grant JW, Ridnour LA, Oberley LW, Swanson PE, Meltzer PS and Trent JM: Increased MnSOD expression suppresses the malignant phenotype of human melanoma cells. Proc. Natl. Acad. Sci. USA, 90:3113-3117, 1993.
2. Li JJ, Oberley LW, St. Clair DK, Ridnour LA and Oberley TD: Phenotypic changes induced in human breast cancer cells by overexpression on manganese-containing superoxide dismutase. Oncogene, 10:1989-2000, 1995.
3. Thomas DD, Espey MG, Ridnour LA, Hofseth LJ, Mancardi D, Harris CC, and Wink DA. Hypoxic inducible factor 1alpha, extracellular signal-regulated kinase, and p53 are regulated by distinct threshold concentrations of nitric oxide. Proc. Natl. Acad. Sci. U S A. 101:8894-99, 2004.
4. Ridnour LA, Oberley, TD, and Oberley LW. Tumor suppressive effects of MnSOD overexpression may involve imbalance in peroxide generation versus peroxide removal. Antioxidants & Redox Signaling, 6(3): 501-12, 2004.
5. Ridnour, LA, Sim, JE, Parsian, AJ, Hunt, CR, Forman, HJ, Goswami, PC, and Spitz, DR. Nitric oxide induced resistance to hydrogen peroxide stress is a glutamate cysteine ligase activity dependent process. Free Radical Biolology & Medicine, 38(10):1360-1370 2005.
6. Isenberg, JS, Ridnour, LA, Perruccio, EM, Espey, MG, Wink, DA, and Roberts, DD. Thrombospondin-1 inhibits endothelial cell responses to nitric oxide in a cGMP-dependent manner. Proc. Natl. Acad. Sci. U S A., 102(37):13141-6, 2005.
7. Ridnour, LA, Isenberg, JS, Espey, MG, Thomas, DD, Roberts, DD, and Wink, DA. Nitric oxide regulates angiogenesis through a functional switch involving thrombospondin-1. Proc. Natl. Acad. Sci. U S A., 102(37):13147-52, 2005.
8. Isenberg JS, Ridnour LA, Dimitry J, Frazier WA, Wink DA, and Roberts DD. CD47 is necessary for inhibition of nitric oxide-stimulated vascular cell responses by thrombospondin-1. J Biol Chem. 281(36):26069-80, 2006.
9. Ridnour LA, Windhausen AN, Isenberg JS, Yeung N, Thomas DD, Vitek MP, Roberts DD, and Wink DA. Nitric Oxide Regulates Matrix Metalloproteinase-9 Activity by Guanylyl Cyclase-dependent and -Independent Pathways. Proc. Natl. Acad. Sci. U S A., 104(43):16898-903, 2007.
10. Isenberg JS, Maxhimer JB, Hyodo F, Pendrak ML, Ridnour LA, DeGraff WG, Tsokos M, Wink DA, Roberts DD. Thrombospondin-1 and CD47 limit cell and tissue survival of radiation injury. Am J Pathol. 173(4):1100-12, 2008.
11. Martin-Manso G, Galli S, Ridnour LA, Tsokos M, Wink DA, Roberts DD. Thrombospondin 1 promotes tumor macrophage recruitment and enhances tumor cell cytotoxicity of differentiated U937 cells. Cancer Res. 68(17):7090-9, 2008.
12. Maxhimer JB, Soto-Pantoja DR, Ridnour LA, Shih HB, Degraff WG, Tsokos M, Wink DA, Isenberg JS, Roberts DD. Radioprotection in normal tissue and delayed tumor growth by blockade of CD47 signaling. Sci Transl Med. 1(3):3ra7, 2009.
13. Weiss JM, Ridnour LA, Back T, Hussain SP, He P, Maciag AE, Keefer LK, Murphy WJ, Harris CC, Wink DA, Wiltrout RH. Macrophage-dependent nitric oxide expression regulates tumor cell detachment and metastasis after IL-2/anti-CD40 immunotherapy. J Exp Med. 207(11):2455-67, 2010.
14. Glynn SA, Boersma BJ, Dorsey TH, Yi M, Yfantis HG, Ridnour LA, Martin DN, Switzer CH, Hudson RS, Wink DA, Lee DH, Stephens RM, Ambs S. Increased NOS2 predicts poor survival in estrogen receptor-negative breast cancer patients. J Clin Invest. 120(11):3843-54, 2010.
15. Glynn SA, Prueitt RL, Ridnour LA, Boersma BJ, Dorsey TM, Wink DA, Goodman JE, Yfantis HG, Lee DH, Ambs S. COX-2 activation is associated with Akt phosphorylation and poor survival in ER-negative, HER2-positive breast cancer. BMC Cancer 10:626, 2010.
16. Wilcock DM, Morgan D, Gordon MN, Taylor TL, Ridnour LA, Wink DA, Colton CA. Activation of matrix metalloproteinases following anti-Abeta immunotherapy; implications for microhemorrhage occurrence. J Neuroinflammation 8(1):115, 2011.
17. Soto-Pantoja DR, Miller TW, Pendrak ML, Degraff WG, Sullivan C, Ridnour LA, Abu-Asab M, Wink DA, Tsokos M, Roberts DD. CD47 deficiency confers cell and tissue radioprotection by activation of autophagy. Autophagy 8(11), 2012.
18. Ridnour LA, Barasch KE, Windhausen AN, Dorsey TM, Yfantis HG, Lee DH, Switzer CH, Glynn SG, Cheng RYS, Ambs S, Wink DA. Nitric oxide synthase and breast cancer: role of TIMP-1 in NO-mediated Akt activation. PLoS ONE 7(9):e44081, 2012.
19. Sohn JJ, Schetter AJ, Yfantis HG, Ridnour LA, Horikawa I, Khan MA, Robles AI, Hussain SP, Goto A, Bowman ED, Hofseth LJ, Bartkova J, Bartek J, Wogan GN, Wink DA, Harris CC. Macrophages, nitric oxide and microRNAs are associated with DNA damage response pathway and senescence in inflammatory bowel disease. PLoS ONE, 7(9):e44156, 2012.
20. Ridnour L, Dhanapal S, Hoos M, Wilson J, Lee J, Cheng R, Brueggemann E, Hines H, Wilcock D, Vitek M, Wink D, Colton C. Nitric Oxide-Mediated Regulation of β-Amyloid Clearance via Alterations of MMP-9/TIMP-1. J Neurochem, 2012.
This page was last updated on 3/5/2013.