Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Aiding and abetting roles of NOX oxidases in cellular transformation

Nature Reviews Cancer volume 12, pages 627–637 (2012)Cite this article

Subjects

Key Points

  • As early as 1981, it was suggested that enzymes biochemically similar to the NADPH oxidase (NOX) NOX2 were present in all cell types, not just in neutrophils. A decade later, high levels of superoxide and hydrogen peroxide were found in various cancer cells, and these levels could be reduced by diphenyleneiodonium (DPI), a chemical inhibitor of flavoprotein-containing enzymes, such as NOX oxidases.

  • The mitochondrial electron transfer chain and NADPH oxidases of the NOX family are the two major sources of reactive oxygen species (ROS) that are implicated in cancer.

  • Seven membrane-bound NOX catalytic isoforms (NOX1–5) and dual oxidase 1 (DUOX1) and DUOX2 have been identified, each of which displays similar but distinct structural, biochemical and subcellular localization characteristics.

  • NOX-dependent redox signalling occurs at cellular membranes and intracellular structures where the NOX catalytic and regulatory subunits are localized. The NOX catalytic subunits NOX2, NOX1, NOX4 and NOX5 have been detected in the plasma membrane. NOX4 has additionally been detected in the endoplasmic reticulum, mitochondrial and nuclear membranes. NOX subunits also reside at specific subcellular microdomains, such as NOX4 at focal adhesions, NOX1 at caveoli and lipid rafts, and NOX1 and NOX4 at invadopodia.

  • NOX catalytic and regulatory subunits have been implicated in one or more of the most common cancer types. Increased mRNA and/or protein expression of NOX1, NOX2, NOX4 and NOX5 or their regulatory components have been detected at higher levels in various cultured cancer cell lines or human tumours compared with normal controls at early and late stages of tumorigenesis, suggesting that ROS derived from NADPH oxidases may be important in both the initiation and the maintenance phases of tumour development.

  • Initial studies indicate that NOX oxidases can effect several of the hallmarks of cancer, including genomic instability, autonomous growth and survival, angiogenesis, invasion and metastasis.

Abstract

NADPH oxidases of the NADPH oxidase (NOX) family are dedicated reactive oxygen species-generating enzymes that broadly and specifically regulate redox-sensitive signalling pathways that are involved in cancer development and progression. They act at specific cellular membranes and microdomains through the activation of oncogenes and the inactivation of tumour suppressor proteins. In this Review, we discuss primary targets and redox-linked signalling systems that are influenced by NOX-derived ROS, and the biological role of NOX oxidases in the aetiology of cancer.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Structure and molecular organization of the NADPH oxidases of the NOX family.
Figure 2: Integration of NOX oxidase-derived ROS with the hallmarks of cancer.
Figure 3: A hypothesis for the function of NOX-derived ROS in the progression of carcinogenesis.

Similar content being viewed by others

References

  1. Knudson, A. G. Two genetic hits (more or less) to cancer. Nature Rev. Cancer 1, 157–162 (2001).

    Article  CAS  Google Scholar 

  2. Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).

    Article  CAS  PubMed  Google Scholar 

  3. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    Article  CAS  PubMed  Google Scholar 

  4. Oberley, L. W., Oberley, T. D. & Buettner, G. R. Cell division in normal and transformed cells: the possible role of superoxide and hydrogen peroxide. Med. Hypotheses 7, 21–42 (1981). The free radical theory of cancer is presented.

    Article  CAS  PubMed  Google Scholar 

  5. McCord, J. M. & Fridovich, I. The utility of superoxide dismutase in studying free radical reactions. I. Radicals generated by the interaction of sulfite, dimethyl sulfoxide, and oxygen. J. Biol. Chem. 244, 6056–6063 (1969). This seminal paper describes the biochemical characterizaiton of superoxide dismutases involved in neutralizing ROS.

    CAS  PubMed  Google Scholar 

  6. Dewald, B., Baggiolini, M., Curnutte, J. T. & Babior, B. M. Subcellular localization of the superoxide-forming enzyme in human neutrophils. J. Clin. Invest. 63, 21–29 (1979).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bittinger, F. et al. Production of superoxide by human malignant melanoma cells. Melanoma Res. 8, 381–387 (1998).

    Article  CAS  PubMed  Google Scholar 

  8. Szatrowski, T. P. & Nathan, C. F. Production of large amounts of hydrogen peroxide by human tumor cells. Cancer Res. 51, 794–798 (1991). This paper describes the detection of diphenyleneiodonium-inhibitable ROS in a large variety of cancer cells.

    CAS  PubMed  Google Scholar 

  9. Ralph, S. J., Rodriguez-Enriquez, S., Neuzil, J., Saavedra, E. & Moreno-Sanchez, R. The causes of cancer revisited: “mitochondrial malignancy” and ROS-induced oncogenic transformation - why mitochondria are targets for cancer therapy. Mol. Aspects Med. 31, 145–170 (2010).

    Article  CAS  PubMed  Google Scholar 

  10. Singh, K. K. Mitochondria damage checkpoint, aging, and cancer. Ann. NY Acad. Sci. 1067, 182–190 (2006).

    Article  CAS  PubMed  Google Scholar 

  11. Wallace, D. C. Mitochondria and cancer: Warburg addressed. Cold Spring Harb. Symp. Quant. Biol. 70, 363–374 (2005).

    Article  CAS  PubMed  Google Scholar 

  12. Barnes, J. L. & Gorin, Y. Myofibroblast differentiation during fibrosis: role of NAD(P)H oxidases. Kidney Int. 79, 944–956 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Bedard, K. & Krause, K. H. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol. Rev. 87, 245–313 (2007). This is an extensive review of the structure and function of NOX oxidases.

    Article  CAS  PubMed  Google Scholar 

  14. Drummond, G. R., Selemidis, S., Griendling, K. K. & Sobey, C. G. Combating oxidative stress in vascular disease: NADPH oxidases as therapeutic targets. Nature Rev. Drug Discov. 10, 453–471 (2011).

    Article  CAS  Google Scholar 

  15. Banfi, B. et al. NOX3, a superoxide-generating NADPH oxidase of the inner ear. J. Biol. Chem. 279, 46065–46072 (2004).

    Article  CAS  PubMed  Google Scholar 

  16. Banfi, B. et al. A mammalian H+ channel generated through alternative splicing of the NADPH oxidase homolog NOH-1. Science 287, 138–142 (2000).

    Article  CAS  PubMed  Google Scholar 

  17. Cheng, G., Cao, Z., Xu, X., van Meir, E. G. & Lambeth, J. D. Homologs of gp91phox: cloning and tissue expression of Nox3, Nox4, and Nox5. Gene 269, 131–140 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. Dupuy, C. et al. Purification of a novel flavoprotein involved in the thyroid NADPH oxidase. Cloning of the porcine and human cdnas. J. Biol. Chem. 274, 37265–37269 (1999).

    Article  CAS  PubMed  Google Scholar 

  19. Geiszt, M. NADPH oxidases: new kids on the block. Cardiovasc. Res. 71, 289–299 (2006).

    Article  CAS  PubMed  Google Scholar 

  20. Geiszt, M., Kopp, J. B., Varnai, P. & Leto, T. L. Identification of renox, an NAD(P)H oxidase in kidney. Proc. Natl Acad. Sci. USA 97, 8010–8014 (2000). This paper describes the cloning of the NOX isoform NOX4 and suggests that NOX4 is an oxygen sensor.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Lambeth, J. D., Kawahara, T. & Diebold, B. Regulation of Nox and Duox enzymatic activity and expression. Free Radic. Biol. Med. 43, 319–331 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Shiose, A. et al. A novel superoxide-producing NAD(P)H oxidase in kidney. J. Biol. Chem. 276, 1417–1423 (2001).

    Article  CAS  PubMed  Google Scholar 

  23. Suh, Y. A. et al. Cell transformation by the superoxide-generating oxidase Mox1. Nature 401, 79–82 (1999). This paper describes the cloning of the NOX isoform NOX1 and provides the first evidence that a NOX oxidase may mediate cellular transformation.

    Article  CAS  PubMed  Google Scholar 

  24. Ginabreda, M. G. et al. Negative correlation between thyroperoxidase and dual oxidase H2O2-generating activities in thyroid nodular lesions. Eur. J. Endocrinol. 158, 223–227 (2008).

    Article  CAS  PubMed  Google Scholar 

  25. Lacroix, L. et al. Expression of nicotinamide adenine dinucleotide phosphate oxidase flavoprotein DUOX genes and proteins in human papillary and follicular thyroid carcinomas. Thyroid 11, 1017–1023 (2001).

    Article  CAS  PubMed  Google Scholar 

  26. Luxen, S., Belinsky, S. A. & Knaus, U. G. Silencing of DUOX NADPH oxidases by promoter hypermethylation in lung cancer. Cancer Res. 68, 1037–1045 (2008).

    Article  CAS  PubMed  Google Scholar 

  27. Block, K., Gorin, Y. & Abboud, H. E. Subcellular localization of Nox4 and regulation in diabetes. Proc. Natl Acad. Sci. USA 106, 14385–14390 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Borregaard, N., Heiple, J. M., Simons, E. R. & Clark, R. A. Subcellular localization of the b-cytochrome component of the human neutrophil microbicidal oxidase: translocation during activation. J. Cell Biol. 97, 52–61 (1983).

    Article  CAS  PubMed  Google Scholar 

  29. Serrander, L. et al. NOX5 is expressed at the plasma membrane and generates superoxide in response to protein kinase C activation. Biochimie 89, 1159–1167 (2007).

    Article  CAS  PubMed  Google Scholar 

  30. Takac, I. et al. The E-loop is involved in hydrogen peroxide formation by the NADPH oxidase Nox4. J. Biol. Chem. 286, 13304–13313 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. von Lohneysen, K., Noack, D., Jesaitis, A. J., Dinauer, M. C. & Knaus, U. G. Mutational analysis reveals distinct features of the Nox4-p22 phox complex. J. Biol. Chem. 283, 35273–35282 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Van Buul, J. D., Fernandez-Borja, M., Anthony, E. C. & Hordijk, P. L. Expression and localization of NOX2 and NOX4 in primary human endothelial cells. Antioxid. Redox Signal. 7, 308–317 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. Ago, T. et al. Upregulation of Nox4 by hypertrophic stimuli promotes apoptosis and mitochondrial dysfunction in cardiac myocytes. Circ. Res. 106, 1253–1264 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Graham, K. A. et al. NADPH oxidase 4 is an oncoprotein localized to mitochondria. Cancer Biol. Ther. 10, 223–231 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Hilenski, L. L., Clempus, R. E., Quinn, M. T., Lambeth, J. D. & Griendling, K. K. Distinct subcellular localizations of Nox1 and Nox4 in vascular smooth muscle cells. Arterioscler. Thromb. Vasc. Biol. 24, 677–683 (2004).

    Article  CAS  PubMed  Google Scholar 

  36. Cheng, G. & Lambeth, J. D. NOXO1, regulation of lipid binding, localization, and activation of Nox1 by the Phox homology (PX) domain. J. Biol. Chem. 279, 4737–4742 (2004).

    Article  CAS  PubMed  Google Scholar 

  37. Diaz, B. et al. Tks5-dependent, nox-mediated generation of reactive oxygen species is necessary for invadopodia formation. Sci. Signal. 2, ra53 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Burnham, D. N., Uhlinger, D. J. & Lambeth, J. D. Diradylglycerol synergizes with an anionic amphiphile to activate superoxide generation and phosphorylation of p47phox in a cell-free system from human neutrophils. J. Biol. Chem. 265, 17550–17559 (1990).

    CAS  PubMed  Google Scholar 

  39. Nauseef, W. M., McCormick, S., Renee, J., Leidal, K. G. & Clark, R. A. Functional domain in an arginine-rich carboxyl-terminal region of p47phox. J. Biol. Chem. 268, 23646–23651 (1993).

    CAS  PubMed  Google Scholar 

  40. Leto, T. L., Morand, S., Hurt, D. & Ueyama, T. Targeting and regulation of reactive oxygen species generation by Nox family NADPH oxidases. Antioxid. Redox Signal 11, 2607–2619 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Martyn, K. D., Frederick, L. M., von Loehneysen, K., Dinauer, M. C. & Knaus, U. G. Functional analysis of Nox4 reveals unique characteristics compared to other NADPH oxidases. Cell. Signal. 18, 69–82 (2006).

    Article  CAS  PubMed  Google Scholar 

  42. Banfi, B., Clark, R. A., Steger, K. & Krause, K. H. Two novel proteins activate superoxide generation by the NADPH oxidase NOX1. J. Biol. Chem. 278, 3510–3513 (2003).

    Article  CAS  PubMed  Google Scholar 

  43. Brandes, R. P. & Schroder, K. Composition and functions of vascular nicotinamide adenine dinucleotide phosphate oxidases. Trends Cardiovasc. Med. 18, 15–19 (2008).

    Article  CAS  PubMed  Google Scholar 

  44. Brandes, R. P., Weissmann, N. & Schroder, K. NADPH oxidases in cardiovascular disease. Free Radic. Biol. Med. 49, 687–706 (2010).

    Article  CAS  PubMed  Google Scholar 

  45. Lassegue, B. & Griendling, K. K. NADPH oxidases: functions and pathologies in the vasculature. Arterioscler Thromb. Vasc. Biol. 30, 653–661 (2010).

    Article  CAS  PubMed  Google Scholar 

  46. Selemidis, S., Sobey, C. G., Wingler, K., Schmidt, H. H. & Drummond, G. R. NADPH oxidases in the vasculature: molecular features, roles in disease and pharmacological inhibition. Pharmacol. Ther. 120, 254–291 (2008).

    Article  CAS  PubMed  Google Scholar 

  47. Lyle, A. N. et al. Poldip2, a novel regulator of Nox4 and cytoskeletal integrity in vascular smooth muscle cells. Circ. Res. 105, 249–259 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Morand, S. et al. Duox maturation factors form cell surface complexes with Duox affecting the specificity of reactive oxygen species generation. FASEB J. 23, 1205–1218 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Block, K. et al. NAD(P)H oxidases regulate HIF-2α protein expression. J. Biol. Chem. 282, 8019–8026 (2007).

    Article  CAS  PubMed  Google Scholar 

  50. Brar, S. S. et al. NOX5 NAD(P)H oxidase regulates growth and apoptosis in DU 145 prostate cancer cells. Am. J. Physiol. Cell Physiol. 285, C353–C369 (2003).

    Article  CAS  PubMed  Google Scholar 

  51. Brar, S. S. et al. An NAD(P)H oxidase regulates growth and transcription in melanoma cells. Am. J. Physiol. Cell Physiol. 282, C1212–C1224 (2002).

    Article  CAS  PubMed  Google Scholar 

  52. Choi, J. A. et al. Pro-survival of estrogen receptor-negative breast cancer cells is regulated by a BLT2-reactive oxygen species-linked signaling pathway. Carcinogenesis 31, 543–551 (2010).

    Article  CAS  PubMed  Google Scholar 

  53. Huang, H. S., Liu, Z. M., Chen, P. C., Tseng, H. Y. & Yeh, B. W. TG-interacting factor-induced superoxide production from NADPH oxidase contributes to the migration/invasion of urothelial carcinoma. Free Radic. Biol Med. (in the press).

  54. Huang, W. C., Li, X., Liu, J., Lin, J. & Chung, L. W. Activation of androgen receptor, lipogenesis, and oxidative stress converged by SREBP-1 is responsible for regulating growth and progression of prostate cancer cells. Mol. Cancer Res. 10, 133–142 (2012).

    Article  CAS  PubMed  Google Scholar 

  55. Juhasz, A. et al. Expression of NADPH oxidase homologues and accessory genes in human cancer cell lines, tumours and adjacent normal tissues. Free Radic. Res. 43, 523–532 (2009). mRNA expression levels of NOX catalytic and regulatory subunits are presented in a large variety of cultured cancer cell lines and tissues and are compared with normal controls.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Kumar, B., Koul, S., Khandrika, L., Meacham, R. B. & Koul, H. K. Oxidative stress is inherent in prostate cancer cells and is required for aggressive phenotype. Cancer Res. 68, 1777–1785 (2008).

    Article  CAS  PubMed  Google Scholar 

  57. Prata, C. et al. Nox-generated ROS modulate glucose uptake in a leukaemic cell line. Free Radic. Res. 42, 405–414 (2008).

    Article  CAS  PubMed  Google Scholar 

  58. Seals, D. F. et al. The adaptor protein Tks5/Fish is required for podosome formation and function, and for the protease-driven invasion of cancer cells. Cancer Cell 7, 155–165 (2005).

    Article  CAS  PubMed  Google Scholar 

  59. Shimada, K., Fujii, T., Anai, S., Fujimoto, K. & Konishi, N. ROS generation via NOX4 and its utility in the cytological diagnosis of urothelial carcinoma of the urinary bladder. BMC Urol. 11, 22 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Vaquero, E. C., Edderkaoui, M., Pandol, S. J., Gukovsky, I. & Gukovskaya, A. S. Reactive oxygen species produced by NAD(P)H oxidase inhibit apoptosis in pancreatic cancer cells. J. Biol. Chem. 279, 34643–34654 (2004). This paper describes the first evidence that NOX4-derived ROS mediates cell survival in cancer cells.

    Article  CAS  PubMed  Google Scholar 

  61. Yamaura, M. et al. NADPH oxidase 4 contributes to transformation phenotype of melanoma cells by regulating G2-M cell cycle progression. Cancer Res. 69, 2647–2654 (2009).

    Article  CAS  PubMed  Google Scholar 

  62. Arnold, R. S. et al. Nox1 expression determines cellular reactive oxygen and modulates c-fos-induced growth factor, interleukin-8, and Cav-1. Am. J. Pathol. 171, 2021–2032 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Bauer, K. M., Hummon, A. B. & Buechler, S. Right-side and left-side colon cancer follow different pathways to relapse. Mol. Carcinog. 51, 411–421 (2012).

    Article  CAS  PubMed  Google Scholar 

  64. Block, K. et al. The NADPH oxidase subunit p22phox inhibits the function of the tumor suppressor protein tuberin. Am. J. Pathol. 176, 2447–2455 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Desouki, M. M., Kulawiec, M., Bansal, S., Das, G. M. & Singh, K. K. Cross talk between mitochondria and superoxide generating NADPH oxidase in breast and ovarian tumors. Cancer Biol. Ther. 4, 1367–1373 (2005). This paper demonstrates the existence of crosstalk between the mitochondria and NADPH oxidase in cancer.

    Article  CAS  PubMed  Google Scholar 

  66. Fritz, G., Just, I. & Kaina, B. Rho GTPases are over-expressed in human tumors. Int. J. Cancer 81, 682–687 (1999).

    Article  CAS  PubMed  Google Scholar 

  67. Fukuyama, M. et al. Overexpression of a novel superoxide-producing enzyme, NADPH oxidase 1, in adenoma and well differentiated adenocarcinoma of the human colon. Cancer Lett. 221, 97–104 (2005).

    Article  CAS  PubMed  Google Scholar 

  68. Gomez del Pulgar, T., Benitah, S. A., Valeron, P. F., Espina, C. & Lacal, J. C. Rho GTPase expression in tumourigenesis: evidence for a significant link. Bioessays 27, 602–613 (2005).

    Article  CAS  PubMed  Google Scholar 

  69. Hoffmann, M. et al. A functional polymorphism in the NAD(P)H oxidase subunit CYBA is related to gene expression, enzyme activity, and outcome in non-Hodgkin lymphoma. Cancer Res. 70, 2328–2338 (2010).

    Article  CAS  PubMed  Google Scholar 

  70. Kamiguti, A. S. et al. Expression and activity of NOX5 in the circulating malignant B cells of hairy cell leukemia. J. Immunol. 175, 8424–8430 (2005).

    Article  CAS  PubMed  Google Scholar 

  71. Lan, Q. et al. Genetic polymorphisms in the oxidative stress pathway and susceptibility to non-Hodgkin lymphoma. Hum. Genet. 121, 161–168 (2007).

    Article  CAS  PubMed  Google Scholar 

  72. Lim, S. D. et al. Increased Nox1 and hydrogen peroxide in prostate cancer. Prostate 62, 200–207 (2005).

    Article  CAS  PubMed  Google Scholar 

  73. Shimada, K. et al. A novel human AlkB homologue, ALKBH8, contributes to human bladder cancer progression. Cancer Res. 69, 3157–3164 (2009).

    Article  CAS  PubMed  Google Scholar 

  74. Weyemi, U. et al. Intracellular expression of reactive oxygen species-generating NADPH oxidase NOX4 in normal and cancer thyroid tissues. Endocr. Relat. Cancer 17, 27–37 (2010).

    Article  CAS  PubMed  Google Scholar 

  75. Xia, C. et al. Reactive oxygen species regulate angiogenesis and tumor growth through vascular endothelial growth factor. Cancer Res. 67, 10823–10830 (2007).

    Article  CAS  PubMed  Google Scholar 

  76. Durak, I., Canbolat, O., Kavutcu, M., Ozturk, H. S. & Yurtarslani, Z. Activities of total, cytoplasmic, and mitochondrial superoxide dismutase enzymes in sera and pleural fluids from patients with lung cancer. J. Clin. Lab. Anal. 10, 17–20 (1996).

    Article  CAS  PubMed  Google Scholar 

  77. Bostwick, D. G. et al. Antioxidant enzyme expression and reactive oxygen species damage in prostatic intraepithelial neoplasia and cancer. Cancer 89, 123–134 (2000).

    Article  CAS  PubMed  Google Scholar 

  78. Curtis, C. D., Thorngren, D. L. & Nardulli, A. M. Immunohistochemical analysis of oxidative stress and DNA repair proteins in normal mammary and breast cancer tissues. BMC Cancer 10, 9 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Evans, P. & Halliwell, B. Free radicals and hearing. Cause, consequence, and criteria. Ann. NY Acad. Sci. 884, 19–40 (1999).

    Article  CAS  PubMed  Google Scholar 

  80. Novo, E. & Parola, M. Redox mechanisms in hepatic chronic wound healing and fibrogenesis. Fibrogenesis Tissue Repair 1, 5 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Kartha, G. K. et al. Renal mitochondrial damage and protein modification in type-2 diabetes. Acta Diabetol. 45, 75–81 (2008).

    Article  CAS  PubMed  Google Scholar 

  82. Spencer, N. Y. et al. Control of hepatic nuclear superoxide production by glucose 6-phosphate dehydrogenase and NADPH oxidase-4. J. Biol. Chem. 286, 8977–8987 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Weyemi, U. et al. ROS-generating NADPH oxidase NOX4 is a critical mediator in oncogenic H-Ras-induced DNA damage and subsequent senescence. Oncogene 31, 1117–1129 (2012).

    Article  CAS  PubMed  Google Scholar 

  84. Burdon, R. H. Superoxide and hydrogen peroxide in relation to mammalian cell proliferation. Free Radic. Biol. Med. 18, 775–794 (1995).

    Article  CAS  PubMed  Google Scholar 

  85. Burdon, R. H., Gill, V. & Rice-Evans, C. Oxidative stress and tumour cell proliferation. Free Radic. Res. Commun. 11, 65–76 (1990).

    Article  CAS  PubMed  Google Scholar 

  86. Burdon, R. H. & Rice-Evans, C. Free radicals and the regulation of mammalian cell proliferation. Free Radic. Res. Commun. 6, 345–358 (1989).

    Article  CAS  PubMed  Google Scholar 

  87. Bae, Y. S. et al. Epidermal growth factor (EGF)-induced generation of hydrogen peroxide. Role in EGF receptor-mediated tyrosine phosphorylation. J. Biol. Chem. 272, 217–221 (1997).

    Article  CAS  PubMed  Google Scholar 

  88. Mahadev, K. et al. The NAD(P)H oxidase homolog Nox4 modulates insulin-stimulated generation of H2O2 and plays an integral role in insulin signal transduction. Mol. Cell. Biol. 24, 1844–1854 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Sundaresan, M., Yu, Z. X., Ferrans, V. J., Irani, K. & Finkel, T. Requirement for generation of H2O2 for platelet-derived growth factor signal transduction. Science 270, 296–299 (1995).

    Article  CAS  PubMed  Google Scholar 

  90. Chen, K., Kirber, M. T., Xiao, H., Yang, Y. & Keaney, J. F. Jr. Regulation of ROS signal transduction by NADPH oxidase 4 localization. J. Cell Biol. 181, 1129–1139 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  91. Lyle, A. N. & Griendling, K. K. Modulation of vascular smooth muscle signaling by reactive oxygen species. Physiology 21, 269–280 (2006).

    Article  CAS  PubMed  Google Scholar 

  92. Mesquita, F. S. et al. Reactive oxygen species mediate mitogenic growth factor signaling pathways in human leiomyoma smooth muscle cells. Biol. Reprod. 82, 341–351 (2010).

    Article  CAS  PubMed  Google Scholar 

  93. Wagner, B. et al. Mitogenic signaling via platelet-derived growth factor β in metanephric mesenchymal cells. J. Am. Soc. Nephrol. 18, 2903–2911 (2007).

    Article  CAS  PubMed  Google Scholar 

  94. Reddy, M. M. et al. NADPH oxidases regulate cell growth and migration in myeloid cells transformed by oncogenic tyrosine kinases. Leukemia 25, 281–289 (2011).

    Article  CAS  PubMed  Google Scholar 

  95. Sastry, S. K. & Elferink, L. A. Checks and balances: interplay of RTKs and PTPs in cancer progression. Biochem. Pharmacol. 82, 435–440 (2011).

    Article  CAS  PubMed  Google Scholar 

  96. Rudolph, T. K. & Freeman, B. A. Transduction of redox signaling by electrophile-protein reactions. Sci. Signal. 2, re7 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Chiarugi, P. & Cirri, P. Redox regulation of protein tyrosine phosphatases during receptor tyrosine kinase signal transduction. Trends Biochem. Sci. 28, 509–514 (2003).

    Article  CAS  PubMed  Google Scholar 

  98. Lee, J. K. et al. NADPH oxidase promotes pancreatic cancer cell survival via inhibiting JAK2 dephosphorylation by tyrosine phosphatases. Gastroenterology 133, 1637–1648 (2007).

    Article  CAS  PubMed  Google Scholar 

  99. Lee, S. R., Kwon, K. S., Kim, S. R. & Rhee, S. G. Reversible inactivation of protein-tyrosine phosphatase 1B in A431 cells stimulated with epidermal growth factor. J. Biol. Chem. 273, 15366–15372 (1998).

    Article  CAS  PubMed  Google Scholar 

  100. Woo, H. A. et al. Reversing the inactivation of peroxiredoxins caused by cysteine sulfinic acid formation. Science 300, 653–656 (2003).

    Article  CAS  PubMed  Google Scholar 

  101. Lou, Y. W. et al. Redox regulation of the protein tyrosine phosphatase PTP1B in cancer cells. FEBS J. 275, 69–88 (2008).

    Article  CAS  PubMed  Google Scholar 

  102. Groen, A. et al. Differential oxidation of protein-tyrosine phosphatases. J. Biol. Chem. 280, 10298–10304 (2005).

    Article  CAS  PubMed  Google Scholar 

  103. Rhee, S. G., Chang, T. S., Bae, Y. S., Lee, S. R. & Kang, S. W. Cellular regulation by hydrogen peroxide. J. Am. Soc. Nephrol. 14, S211–S215 (2003).

    Article  CAS  PubMed  Google Scholar 

  104. Wright, V. P., Reiser, P. J. & Clanton, T. L. Redox modulation of global phosphatase activity and protein phosphorylation in intact skeletal muscle. J. Physiol. 587, 5767–5781 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Chan, E. C., Jiang, F., Peshavariya, H. M. & Dusting, G. J. Regulation of cell proliferation by NADPH oxidase-mediated signaling: potential roles in tissue repair, regenerative medicine and tissue engineering. Pharmacol. Ther. 122, 97–108 (2009).

    Article  CAS  PubMed  Google Scholar 

  106. Ushio-Fukai, M. Localizing NADPH oxidase-derived ROS. Sci. STKE 2006, re8 (2006).

    PubMed  Google Scholar 

  107. Almo, S. C. et al. Structural genomics of protein phosphatases. J. Struct. Funct. Genomics 8, 121–140 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Sancho, P. & Fabregat, I. NADPH oxidase NOX1 controls autocrine growth of liver tumor cells through up-regulation of the epidermal growth factor receptor pathway. J. Biol. Chem. 285, 24815–24824 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Nitsche, C. et al. The phosphatase PHLPP1 regulates Akt2, promotes pancreatic cancer cell death, and inhibits tumor formation. Gastroenterology 142, 377–387.e5 (2012).

    Article  CAS  PubMed  Google Scholar 

  110. Naughton, R., Quiney, C., Turner, S. D. & Cotter, T. G. Bcr-Abl-mediated redox regulation of the PI3K/AKT pathway. Leukemia 23, 1432–1440 (2009).

    Article  CAS  PubMed  Google Scholar 

  111. Seo, J. M. et al. Up-regulation of BLT2 is critical for the survival of bladder cancer cells. Exp. Mol. Med. 43, 129–137 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Mochizuki, T. et al. Inhibition of NADPH oxidase 4 activates apoptosis via the AKT/apoptosis signal-regulating kinase 1 pathway in pancreatic cancer PANC-1 cells. Oncogene 25, 3699–3707 (2006).

    Article  CAS  PubMed  Google Scholar 

  113. Luo, J. et al. Negative control of p53 by Sir2α promotes cell survival under stress. Cell 107, 137–148 (2001).

    Article  CAS  PubMed  Google Scholar 

  114. Puca, R. et al. Nox1 is involved in p53 deacetylation and suppression of its transcriptional activity and apoptosis. Free Radic. Biol. Med. 48, 1338–1346 (2010). This is the first example that NOX1 activates SIRT1 deacetylase, which inhibits p53-dependent cell apoptosis.

    Article  CAS  PubMed  Google Scholar 

  115. Vaziri, H. et al. hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell 107, 149–159 (2001).

    Article  CAS  PubMed  Google Scholar 

  116. Olmos, Y., Brosens, J. J. & Lam, E. W. Interplay between SIRT proteins and tumour suppressor transcription factors in chemotherapeutic resistance of cancer. Drug Resist. Updat. 14, 35–44 (2011).

    Article  CAS  PubMed  Google Scholar 

  117. Frescas, D., Valenti, L. & Accili, D. Nuclear trapping of the forkhead transcription factor FoxO1 via Sirt-dependent deacetylation promotes expression of glucogenetic genes. J. Biol. Chem. 280, 20589–20595 (2005).

    Article  CAS  PubMed  Google Scholar 

  118. Laurent, E. et al. Nox1 is over-expressed in human colon cancers and correlates with activating mutations in K-Ras. Int. J. Cancer 123, 100–107 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Heo, J. Redox control of GTPases: from molecular mechanisms to functional significance in health and disease. Antioxid. Redox Signal. 14, 689–724 (2011).

    Article  CAS  PubMed  Google Scholar 

  120. Lander, H. M. Ogiste, J.S., Teng, K.K. & Novogrodsky, A. p21ras as a common signaling target of reactive free radicals and cellular redox stress. J. Biol. Chem. 270, 21195–21198 (1995).

    Article  CAS  PubMed  Google Scholar 

  121. Adachi, Y. et al. Oncogenic Ras upregulates NADPH oxidase 1 gene expression through MEK-ERK-dependent phosphorylation of GATA-6. Oncogene 27, 4921–4932 (2008).

    Article  CAS  PubMed  Google Scholar 

  122. Mitsushita, J., Lambeth, J. D. & Kamata, T. The superoxide-generating oxidase Nox1 is functionally required for Ras oncogene transformation. Cancer Res. 64, 3580–3585 (2004). This paper describes the cooperation of RAS and NOX1 in cellular transformation.

    Article  CAS  PubMed  Google Scholar 

  123. Kajla, S. et al. A crucial role for Nox 1 in redox-dependent regulation of Wnt-β-catenin signaling. FASEB J. 26, 2049–2059 (2012).

    Article  CAS  PubMed  Google Scholar 

  124. Rimerman, R. A., Gellert-Randleman, A. & Diehl, J. A. Wnt1 and MEK1 cooperate to promote cyclin D1 accumulation and cellular transformation. J. Biol. Chem. 275, 14736–14742 (2000).

    Article  CAS  PubMed  Google Scholar 

  125. Du, J. et al. Regulation of pancreatic cancer growth by superoxide. Mol. Carcinog. 5 Mar 2012 (doi:10.1002/mc.21891).

  126. Cantley, L. C. The phosphoinositide 3-kinase pathway. Science 296, 1655–1657 (2002).

    Article  CAS  PubMed  Google Scholar 

  127. Luo, J., Manning, B. D. & Cantley, L. C. Targeting the PI3K-Akt pathway in human cancer: rationale and promise. Cancer Cell 4, 257–262 (2003).

    Article  CAS  PubMed  Google Scholar 

  128. Manning, B. D. & Cantley, L. C. AKT/PKB signaling: navigating downstream. Cell 129, 1261–1274 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Pópulo, H., Lopes, J. M. & Soares, P. The mTOR signalling pathway in human cancer. Int. J. Mol. Sci. 13, 1886–1918 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Porta, C. & Figlin, R. A. Phosphatidylinositol-3-kinase/Akt signaling pathway and kidney cancer, and the therapeutic potential of phosphatidylinositol-3-kinase/Akt inhibitors. J. Urol. 182, 2569–2577 (2009).

    Article  CAS  PubMed  Google Scholar 

  131. Silvera, D., Formenti, S. C. & Schneider, R. J. Translational control in cancer. Nature Rev. Cancer 10, 254–266 (2010).

    Article  CAS  Google Scholar 

  132. Lee, S. R. et al. Reversible inactivation of the tumor suppressor PTEN by H2O2. J. Biol. Chem. 277, 20336–20342 (2002).

    Article  CAS  PubMed  Google Scholar 

  133. Coant, N. et al. NADPH oxidase 1 modulates WNT and NOTCH1 signaling to control the fate of proliferative progenitor cells in the colon. Mol. Cell. Biol. 30, 2636–2650 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Cui, W. et al. NOX1/nicotinamide adenine dinucleotide phosphate, reduced form (NADPH) oxidase promotes proliferation of stellate cells and aggravates liver fibrosis induced by bile duct ligation. Hepatology 54, 949–958 (2011).

    Article  CAS  PubMed  Google Scholar 

  135. Kwon, J. et al. Reversible oxidation and inactivation of the tumor suppressor PTEN in cells stimulated with peptide growth factors. Proc. Natl Acad. Sci. USA 101, 16419–16424 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Nisbet, R. E. et al. Rosiglitazone attenuates chronic hypoxia-induced pulmonary hypertension in a mouse model. Am. J. Respir. Cell Mol. Biol. 42, 482–490 (2010).

    Article  CAS  PubMed  Google Scholar 

  137. Gan, X., Wang, J., Su, B. & Wu, D. Evidence for direct activation of mTORC2 kinase activity by phosphatidylinositol 3,4,5-trisphosphate. J. Biol. Chem. 286, 10998–11002 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Lamouille, S., Connolly, E., Smyth, J. W., Akhurst, R. J. & Derynck, R. TGF-β-induced activation of mTOR complex 2 drives epithelial-mesenchymal transition and cell invasion. J. Cell Sci. 125, 1259–1273 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Zinzalla, V., Stracka, D., Oppliger, W. & Hall, M. N. Activation of mTORC2 by association with the ribosome. Cell 144, 757–768 (2011).

    Article  CAS  PubMed  Google Scholar 

  140. Plas, D. R. & Thompson, C. B. Akt activation promotes degradation of tuberin and FOXO3a via the proteasome. J. Biol. Chem. 278, 12361–12366 (2003).

    Article  CAS  PubMed  Google Scholar 

  141. Sonenberg, N. Translation factors as effectors of cell growth and tumorigenesis. Curr. Opin. Cell Biol. 5, 955–960 (1993).

    Article  CAS  PubMed  Google Scholar 

  142. Clifford, S. C. et al. The pVHL-associated SCF ubiquitin ligase complex: molecular genetic analysis of elongin B and C, Rbx1 and HIF-1α in renal cell carcinoma. Oncogene 20, 5067–5074 (2001).

    Article  CAS  PubMed  Google Scholar 

  143. Kaelin, W. G. Jr. The von hippel-lindau tumor suppressor protein: an update. Methods Enzymol. 435, 371–383 (2007).

    Article  CAS  PubMed  Google Scholar 

  144. Pause, A. et al. The von Hippel-Lindau tumor-suppressor gene product forms a stable complex with human CUL-2, a member of the Cdc53 family of proteins. Proc. Natl Acad. Sci. USA 94, 2156–2161 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Min, J. H. et al. Structure of an HIF-1α -pVHL complex: hydroxyproline recognition in signaling. Science 296, 1886–1889 (2002).

    Article  CAS  PubMed  Google Scholar 

  146. Maranchie, J. K. & Zhan, Y. Nox4 is critical for hypoxia-inducible factor 2-α transcriptional activity in von Hippel-Lindau-deficient renal cell carcinoma. Cancer Res. 65, 9190–9193 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Isaacs, J. S. et al. HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. Cancer Cell 8, 143–153 (2005).

    Article  CAS  PubMed  Google Scholar 

  148. Sudarshan, S. et al. Fumarate hydratase deficiency in renal cancer induces glycolytic addiction and hypoxia-inducible transcription factor 1α stabilization by glucose-dependent generation of reactive oxygen species. Mol. Cell. Biol. 29, 4080–4090 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Maraldi, T. et al. VEGF-induced ROS generation from NAD(P)H oxidases protects human leukemic cells from apoptosis. Int. J. Oncol. 36, 1581–1589 (2010).

    CAS  PubMed  Google Scholar 

  150. Ushio-Fukai, M. & Nakamura, Y. Reactive oxygen species and angiogenesis: NADPH oxidase as target for cancer therapy. Cancer Lett. 266, 37–52 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Diebold, I., Petry, A., Hess, J. & Gorlach, A. The NADPH oxidase subunit NOX4 is a new target gene of the hypoxia-inducible factor-1. Mol. Biol. Cell 21, 2087–2096 (2010). This is the first paper to show that hypoxia-inducible factors regulate NOX4 gene expression.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Diebold, I. et al. The HIF1 target gene NOX2 promotes angiogenesis through urotensin-II. J. Cell Sci. 125, 956–964 (2012).

    Article  CAS  PubMed  Google Scholar 

  153. Goyal, P. et al. Upregulation of NAD(P)H oxidase 1 in hypoxia activates hypoxia-inducible factor 1 via increase in reactive oxygen species. Free Radic. Biol. Med. 36, 1279–1288 (2004).

    Article  CAS  PubMed  Google Scholar 

  154. Tojo, T. et al. Role of gp91phox (Nox2)-containing NAD(P)H oxidase in angiogenesis in response to hindlimb ischemia. Circulation 111, 2347–2355 (2005).

    Article  CAS  PubMed  Google Scholar 

  155. Vallet, P. et al. Neuronal expression of the NADPH oxidase NOX4, and its regulation in mouse experimental brain ischemia. Neuroscience 132, 233–238 (2005).

    Article  CAS  PubMed  Google Scholar 

  156. Arbiser, J. L. et al. Reactive oxygen generated by Nox1 triggers the angiogenic switch. Proc. Natl Acad. Sci. USA 99, 715–720 (2002). This paper is the first evidence that NOX1 is involved in tumour angiogenesis in vitro and in vivo.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Govindarajan, B. et al. Overexpression of Akt converts radial growth melanoma to vertical growth melanoma. J. Clin. Invest. 117, 719–729 (2007). This paper describes the cooperation of AKT and NOX4 in invasive melanoma cell growth.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Komatsu, D., Kato, M., Nakayama, J., Miyagawa, S. & Kamata, T. NADPH oxidase 1 plays a critical mediating role in oncogenic Ras-induced vascular endothelial growth factor expression. Oncogene 27, 4724–4732 (2008).

    Article  CAS  PubMed  Google Scholar 

  159. Garrido-Urbani, S. et al. Targeting vascular NADPH oxidase 1 blocks tumor angiogenesis through a PPARα mediated mechanism. PLoS ONE 6, e14665 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Tobar, N., Guerrero, J., Smith, P. C. & Martinez, J. NOX4-dependent ROS production by stromal mammary cells modulates epithelial MCF-7 cell migration. Br. J. Cancer 103, 1040–1047 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Hou, Z., Falcone, D. J., Subbaramaiah, K. & Dannenberg, A. J. Macrophages induce COX-2 expression in breast cancer cells: role of IL-1β autoamplification. Carcinogenesis 32, 695–702 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Fitzgerald, J. P. et al. Nox4 mediates renal cell carcinoma cell invasion through hypoxia-induced interleukin 6- and 8- production. PLoS ONE 7, e30712 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Corzo, C. A. et al. Mechanism regulating reactive oxygen species in tumor-induced myeloid-derived suppressor cells. J. Immunol. 182, 5693–5701 (2009).

    Article  CAS  PubMed  Google Scholar 

  164. Courtneidge, S. A. Cell migration and invasion in human disease: the Tks adaptor proteins. Biochem. Soc. Trans. 40, 129–132 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Diaz, B. & Courtneidge, S. A. Redox signaling at invasive microdomains in cancer cells. Free Rad. Biol. Med. 52, 247–256 (2012). This review outlines redox signalling events mediated by invadopodia NADPH oxidase complexes and their contribution to cancer cell invasion.

    CAS  Google Scholar 

  166. Wang, Y. & McNiven, M. A. Invasive matrix degradation at focal adhesions occurs via protease recruitment by a FAK-p130Cas complex. J. Cell Biol. 196, 375–385 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Destaing, O., Block, M. R., Planus, E. & Albiges-Rizo, C. Invadosome regulation by adhesion signaling. Curr. Opin. Cell Biol. 23, 597–606 (2011).

    Article  CAS  PubMed  Google Scholar 

  168. Giannoni, E., Taddei, M. L. & Chiarugi, P. Src redox regulation: again in the front line. Free Radic. Biol. Med. 49, 516–527 (2010).

    Article  CAS  PubMed  Google Scholar 

  169. Guarino, M. Src signaling in cancer invasion. J. Cell. Physiol. 223, 14–26 (2010).

    CAS  PubMed  Google Scholar 

  170. Yeatman, T. J. A renaissance for SRC. Nature Rev. Cancer 4, 470–480 (2004).

    Article  CAS  Google Scholar 

  171. Gianni, D., Taulet, N., DerMardirossian, C. & Bokoch, G. M. c-Src-mediated phosphorylation of NoxA1 and Tks4 induces the reactive oxygen species (ROS)-dependent formation of functional invadopodia in human colon cancer cells. Mol. Biol. Cell 21, 4287–4298 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Baumer, A. T. et al. Phosphatidylinositol 3-kinase-dependent membrane recruitment of Rac-1 and p47phox is critical for α-platelet-derived growth factor receptor-induced production of reactive oxygen species. J. Biol. Chem. 283, 7864–7876 (2008).

    Article  CAS  PubMed  Google Scholar 

  173. Chowdhury, A. K. et al. Src-mediated tyrosine phosphorylation of p47phox in hyperoxia-induced activation of NADPH oxidase and generation of reactive oxygen species in lung endothelial cells. J. Biol. Chem. 280, 20700–20711 (2005).

    Article  CAS  PubMed  Google Scholar 

  174. Gianni, D., Bohl, B., Courtneidge, S. A. & Bokoch, G. M. The involvement of the tyrosine kinase c-Src in the regulation of reactive oxygen species generation mediated by NADPH oxidase-1. Mol. Biol. Cell 19, 2984–2994 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Gianni, D. et al. Novel p47(phox)-related organizers regulate localized NADPH oxidase 1 (Nox1) activity. Sci. Signal. 2, ra54 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Block, K. et al. Nox4 NAD(P)H oxidase mediates Src-dependent tyrosine phosphorylation of PDK-1 in response to angiotensin II: role in mesangial cell hypertrophy and fibronectin expression. J. Biol. Chem. 283, 24061–24076 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Li, Q., Zhang, Y., Marden, J. J., Banfi, B. & Engelhardt, J. F. Endosomal NADPH oxidase regulates c-Src activation following hypoxia/reoxygenation injury. Biochem. J. 411, 531–541 (2008).

    Article  CAS  PubMed  Google Scholar 

  178. Binker, M. G., Binker-Cosen, A. A., Richards, D., Oliver, B. & Cosen-Binker, L. I. EGF promotes invasion by PANC-1 cells through Rac1/ROS-dependent secretion and activation of MMP-2. Biochem. Biophys. Res. Commun. 379, 445–450 (2009).

    Article  CAS  PubMed  Google Scholar 

  179. Steinbrenner, H. et al. Tumor promoter TPA stimulates MMP-9 secretion from human keratinocytes by activation of superoxide-producing NADPH oxidase. Free Radic. Res. 39, 245–253 (2005).

    Article  CAS  PubMed  Google Scholar 

  180. Yoon, S. O., Park, S. J., Yoon, S. Y., Yun, C. H. & Chung, A. S. Sustained production of H2O2 activates pro-matrix metalloproteinase-2 through receptor tyrosine kinases/phosphatidylinositol 3-kinase/NF-κ B pathway. J. Biol. Chem. 277, 30271–30282 (2002).

    Article  CAS  PubMed  Google Scholar 

  181. Grote, K. et al. Mechanical stretch enhances mRNA expression and proenzyme release of matrix metalloproteinase-2 (MMP-2) via NAD(P)H oxidase-derived reactive oxygen species. Circ. Res. 92, e80–e86 (2003).

    Article  CAS  PubMed  Google Scholar 

  182. Seo, J. M., Park, S. & Kim, J. H. Leukotriene B4 receptor-2 promotes invasiveness and metastasis of ovarian cancer cells through signal transducer and activator of transcription 3 (STAT3)-dependent up-regulation of matrix metalloproteinase 2. J. Biol. Chem. 287, 13840–13849 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Choi, J. A., Kim, E. Y., Song, H., Kim, C. & Kim, J. H. Reactive oxygen species are generated through a BLT2-linked cascade in Ras-transformed cells. Free Radic. Biol. Med. 44, 624–634 (2008).

    Article  CAS  PubMed  Google Scholar 

  184. Kim, E. Y., Seo, J. M., Cho, K. J. & Kim, J. H. Ras-induced invasion and metastasis are regulated by a leukotriene B4 receptor BLT2-linked pathway. Oncogene 29, 1167–1178 (2010).

    Article  CAS  PubMed  Google Scholar 

  185. Kim, E. Y. et al. BLT2 promotes the invasion and metastasis of aggressive bladder cancer cells through a reactive oxygen species-linked pathway. Free Radic. Biol. Med. 49, 1072–1081 (2010).

    Article  CAS  PubMed  Google Scholar 

  186. Shinohara, M. et al. Reactive oxygen generated by NADPH oxidase 1 (Nox1) contributes to cell invasion by regulating matrix metalloprotease-9 production and cell migration. J. Biol. Chem. 285, 4481–4488 (2010).

    Article  CAS  PubMed  Google Scholar 

  187. Yang, J. Q. et al. v-Ha-RaS oncogene upregulates the 92-kDa type IV collagenase (MMP-9) gene by increasing cellular superoxide production and activating NF-κB. Free Radic. Biol. Med. 31, 520–529 (2001).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors acknowledge H. E. Abboud, R. A. Clark and R. Li for critical reading of the Review and F. Wauquier for unconditional assistance. Supported by Veterans Administration Career Development Award, NIH R01 NCI CA131272 (K.B.).

Author information

Authors and Affiliations

  1. Audie L. Murphy Memorial Hospital Division, Department of Medicine MC 7882, South Texas Veterans Health Care System, 7703 Floyd Curl Drive, San Antonio, 78229–73900, Texas, USA

    Karen Block

  2. Department of Medicine MC 7882, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, 78229–73900, Texas, USA

    Karen Block & Yves Gorin

Authors
  1. Karen Block
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yves Gorin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Karen Block.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Glossary

Focal adhesions

Specific types of large macromolecular assemblies through which both mechanical force and regulatory signals are transmitted.

Invadopodia

Protrusions of the plasma membrane that contain adhesive proteins and proteolytic enzymes.

Dismutation

A specific type of redox reaction in which a species is simultaneously reduced and oxidized to form two different products, in this case molecular oxygen and hydrogen peroxide.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Block, K., Gorin, Y. Aiding and abetting roles of NOX oxidases in cellular transformation. Nat Rev Cancer 12, 627–637 (2012). https://doi.org/10.1038/nrc3339

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc3339

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer