Nicotinamide adenine dinucleotide phosphate oxidase is differentially regulated in normal myometrium versus leiomyoma.

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This study found that nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) expression was increased in uterine fibroids compared to normal myometrium, with other NOX family members showing differential regulation that may contribute to a prooxidant state in fibroids.

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Abstract

Uterine fibroids are the most common benign tumor in women. The goal of this study was to investigate whether nicotinamide adenine dinucleotide phosphate oxidase (NOX), a major source of superoxide and subsequent oxidative stress, was differentially regulated in myometrium versus leiomyoma. Expression levels of NOXs1-5, dual oxidase (DUOX), DUOX2, NOX organizer (NOXO) 1, NOX activator 1, p47(phox), p67(phox), and p22(phox) were determined in cells treated with hypoxia by real-time reverse transcription-polymerase chain reaction, Western blot, and immunohistochemistry in tissues. Expression of NOX4 increased in fibroid compared to myometrial tissues and cells. The NOX2, DUOX1, and p67(phox) were higher while p22(phox) was lower in fibroid than that in myometrial cells. Hypoxia increased NOX4, DUOX1, and NOXO1 and decreased p22(phox) in myometrial and reduced DUOX1 in fibroid cells. The NOX1, NOX3, NOX5, and DUOX2 were undetectable. Fibroid cells are characterized by a unique NOX profile, which promotes a severe prooxidant state that may be responsible for their development. Targeting these subunits may be beneficial for future therapeutic interventions.
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Abstract

Uterine fibroids are the most common benign tumor in women. The goal of this study was to investigate whether nicotinamide adenine dinucleotide phosphate oxidase (NOX), a major source of superoxide and subsequent oxidative stress, was differentially regulated in myometrium versus leiomyoma. Expression levels of NOXs1-5, dual oxidase (DUOX), DUOX2, NOX organizer (NOXO) 1, NOX activator 1, p47phox, p67phox, and p22phox were determined in cells treated with hypoxia by real-time reverse transcription-polymerase chain reaction, Western blot, and immunohistochemistry in tissues. Expression of NOX4 increased in fibroid compared to myometrial tissues and cells. The NOX2, DUOX1, and p67phox were higher while p22phox was lower in fibroid than that in myometrial cells. Hypoxia increased NOX4, DUOX1, and NOXO1 and decreased p22phox in myometrial and reduced DUOX1 in fibroid cells. The NOX1, NOX3, NOX5, and DUOX2 were undetectable. Fibroid cells are characterized by a unique NOX profile, which promotes a severe prooxidant state that may be responsible for their development. Targeting these subunits may be beneficial for future therapeutic interventions. Similar content being viewed by others

References

Yoshino O, Hayashi T, Osuga Y, et al. Decreased pregnancy rate is linked to abnormal uterine peristalsis caused by intramural fibroids. Hum Reprod. 2010;25(10):2475–2479. Bulman JC, Ascher SM, Spies JB. Current concepts in uterine fibroid embolization. Radiographics. 2012;32(6):1735–1750. Sahin K, Ozercan R, Onderci M, et al. Lycopene supplementation prevents the development of spontaneous smooth muscle tumors of the oviduct in Japanese quail. Nutr Cancer. 2004;50(2):181–189. Evans P, Brunsell S. Uterine fibroid tumors: diagnosis and treatment. Am Fam Physician. 2007;75(10):1503–1508. Alpay Z, Saed GM, Diamond MP. Female infertility and free radicals: potential role in adhesions and endometriosis. J Soc Gynecol Investig. 2006;13(6):390–398. Ara C, Kirimlioglu H, Karabulut AB, et al. Protective effect of melatonin against oxidative stress on adhesion formation in the rat cecum and uterine horn model. Life Sci. 2005;77(12):1341–1350. Vural M, Camuzcuoglu H, Toy H, Camuzcuoglu A, Aksoy N. Oxidative stress and prolidase activity in women with uterine fibroids. J Obstet Gynaecol. 2012;32(1):68–72. Rahman K. Studies on free radicals, antioxidants, and co-factors. Clin Interv Aging. 2007;2(2):219–236. Fruehauf JP, Meyskens FL Jr. Reactive oxygen species: a breath of life or death? Clin Cancer Res. 2007;13(3):789–794. Tal R, Segars JH. The role of angiogenic factors in fibroid pathogenesis: potential implications for future therapy [published online September 29, 2013]. Hum Reprod Update. 2013. Mesquita FS, Dyer SN, Heinrich DA, Bulun SE, Marsh EE, Nowak RA. Reactive oxygen species mediate mitogenic growth factor signaling pathways in human leiomyoma smooth muscle cells. Biol Reprod. 2010;82(2):341–351. Bedard K, Krause KH. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev. 2007;87(1):245–313. Meier B, Cross AR, Hancock JT, Kaup FJ, Jones OT. Identification of a superoxide-generating NADPH oxidase system in human fibroblasts. Biochem J. 1991;275(pt 1):241–245. Szatrowski TP, Nathan CF. Production of large amounts of hydrogen peroxide by human tumor cells. Cancer Res. 1991;51(3): 794–798. Griendling KK, Minieri CA, Ollerenshaw JD, Alexander RW. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res. 1994;74(6): 1141–1148. Dong J, Sulik KK, Chen SY. The role of NOX enzymes in ethanol-induced oxidative stress and apoptosis in mouse embryos. Toxicol Lett. 2010;193(1):94–100. Lambeth JD. NOX enzymes and the biology of reactive oxygen. Nat Rev Immunol. 2004;4(3):181–189. Lassegue B, San Martin A, Griendling KK. Biochemistry, physiology, and pathophysiology of NADPH oxidases in the cardiovascular system. Circ Res. 2012;110(10):1364–1390. Clark RA, Epperson TK, Valente AJ. Mechanisms of activation of NADPH oxidases. Jpn J Infect Dis. 2004;57(5): S22–23. Valencia A, Sapp E, Kimm JS, et al. Elevated NADPH oxidase activity contributes to oxidative stress and cell death in Huntington’s disease. Hum Mol Genet. 2013;22(6):1112–1131. Tammariello SP, Quinn MT, Estus S. NADPH oxidase contributes directly to oxidative stress and apoptosis in nerve growth factor-deprived sympathetic neurons. J Neurosci. 2000;20(1): RC53. Perianayagam MC, Liangos O, Kolyada AY, et al. NADPH oxidase p22phox and catalase gene variants are associated with bio-markers of oxidative stress and adverse outcomes in acute renal failure. J Am Soc Nephrol. 2007;18(1):255–263. Carney SA, Tahara H, Swartz CD, et al. Immortalization of human uterine leiomyoma and myometrial cell lines after induction of telomerase activity: molecular and phenotypic characteristics. Lab Invest. 2002;82(6):719–728. Al-Hendy A, Lee EJ, Wang HQ, Copland JA. Gene therapy of uterine leiomyomas: adenovirus-mediated expression of dominant negative estrogen receptor inhibits tumor growth in nude mice. Am J Obstet Gynecol. 2004;191(5):1621–1631. Hassan MH, Salama SA, Arafa HM, Hamada FM, Al-Hendy A. Adenovirus-mediated delivery of a dominant-negative estrogen receptor gene in uterine leiomyoma cells abrogates estrogen- and progesterone-regulated gene expression. J Clin Endocrinol Metab. 2007;92(10):3949–3957. Jiang Z, Fletcher NM, Ali-Fehmi R, et al. Modulation of redox signaling promotes apoptosis in epithelial ovarian cancer cells. Gynecol Oncol. 2011;122(2):418–423. Paavilainen L, Edvinsson A, Asplund A, et al. The impact of tissue fixatives on morphology and antibody-based protein profiling in tissues and cells. J Histochem Cytochem. 2010;58(3):237–246. White JC, Jiang ZL, Diamond MP, Saed GM. Macrophages induce the adhesion phenotype in normal peritoneal fibroblasts. Fertil Steril. 2011;96(3):758–763.e753. Zhou S, Yi T, Shen K, Zhang B, Huang F, Zhao X. Hypoxia: the driving force of uterine myometrial stem cells differentiation into leiomyoma cells. Med Hypotheses. 2011;77(6):985–986. Inoue M, Sato EF, Nishikawa M, et al. Mitochondrial generation of reactive oxygen species and its role in aerobic life. Curr Med Chem. 2003;10(23):2495–2505. Fletcher NM, Jiang ZL, Diamond MP, Abu-Soud HM, Saed GM. Hypoxia-generated superoxide induces the development of the adhesion phenotype. Free Radic Biol Med. 2008;45(4):530–536. Cao X, Dai X, Parker LM, Kreulen DL. Differential regulation of NADPH oxidase in sympathetic and sensory ganglia in deoxycorticosterone acetate salt hypertension. Hypertension. 2007;50(4): 663–671. Hsieh CH, Shyu WC, Chiang CY, Kuo JW, Shen WC, Liu RS. NADPH oxidase subunit 4-mediated reactive oxygen species contribute to cycling hypoxia-promoted tumor progression in glioblastoma multiforme. PLoS One. 2011;6(9):e23945. Graham KA, Kulawiec M, Owens KM, et al. NADPH oxidase 4 is an oncoprotein localized to mitochondria. Cancer Biol Ther. 2010;10(3):223–231. Burdon RH. Superoxide and hydrogen peroxide in relation to mammalian cell proliferation. Free Radic Biol Med. 1995; 18(4):775–794. Gorin Y, Ricono JM, Kim NH, Bhandari B, Choudhury GG, Abboud HE. Nox4 mediates angiotensin II-induced activation of Akt/protein kinase B in mesangial cells. Am J Physiol Renal Physiol. 2003;285(2):F219–F229. Cucoranu I, Clempus R, Dikalova A, et al. NAD(P)H oxidase 4 mediates transforming growth factor-beta1-induced differentiation of cardiac fibroblasts into myofibroblasts. Circ Res. 2005; 97(9):900–907. Sturrock A, Cahill B, Norman K, et al. Transforming growth factor-beta1 induces Nox4 NAD(P)H oxidase and reactive oxygen species-dependent proliferation in human pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 2006;290(4):L661–L673. Datla SR, Peshavariya H, Dusting GJ, Mahadev K, Goldstein BJ, Jiang F. Important role of Nox4 type NADPH oxidase in angiogenic responses in human microvascular endothelial cells in vitro. Arterioscler Thromb Vasc Biol. 2007;27(11):2319–2324. Rigutto S, Hoste C, Grasberger H, et al. Activation of dual oxidases Duox1 and Duox2: differential regulation mediated by camp-dependent protein kinase and protein kinase C-dependent phosphorylation. J Biol Chem. 2009;284(11):6725–6734. Lee YM, Kim BJ, Chun YS, et al. NOX4 as an oxygen sensor to regulate TASK-1 activity. Cell Signal. 2006;18(4):499–507. Martyn KD, Frederick LM, von Loehneysen K, Dinauer MC, Knaus UG. Functional analysis of Nox4 reveals unique characteristics compared to other NADPH oxidases. Cell Signal. 2006; 18(1):69–82. Sumimoto H, Miyano K, Takeya R. Molecular composition and regulation of the Nox family NAD(P)H oxidases. Biochem Biophys Res Commun. 2005;338(1):677–686. Babior BM, Lambeth JD, Nauseef W. The neutrophil NADPH oxidase. Arch Biochem Biophys. 2002;397(2):342–344. Author information Authors and Affiliations Corresponding author Rights and permissions About this article Cite this article Fletcher, N.M., Saed, M.G., Abuanzeh, S. et al. Nicotinamide Adenine Dinucleotide Phosphate Oxidase Is Differentially Regulated in Normal Myometrium Versus Leiomyoma. Reprod. Sci. 21, 1145–1152 (2014). https://doi.org/10.1177/1933719114522552 Published: Issue date: DOI: https://doi.org/10.1177/1933719114522552

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