Role of NADPH oxidase-mediated ROS generation in skin tumorigenesis and aging
keywords: xeroderma pigmentosum, DNA repair, NADPH oxidase, skin cancers, skin aging
NADPH oxidase is normally quiescent, but generates a large amount of superoxide anion radical (ROS) upon activation via the one electron-reduction of oxygen by NADPH. The NOX proteins are involved in host defense, post-translational processing of proteins, cellular signaling, regulation of gene expression, and cellular differentiation. NOX isozymes have been shown to increase in association with ROS production and tumorigenicity in various cancer cells. Recently we have shown that keratinocytes from Xeroderma Pigmentosum patients (XPC) and normal human keratinocytes following XPC knockdown displayed an increased proliferative capacity and were capable of forming skin cancer (SCCs) in immunodeficient mice. The critical step in tumoral transformation of XPC knockdown keratinocytes was the increased activity of NOX1 and the subsequent increase in ROS production. The tumorigenic potency of XPC knock-down cells was abrogated by NOX1 silencing. We have further found that premature aging features in Xpc-/- mice were mostly rescued by inhibition of NADPH oxidase 1 (NOX1) activity using a novel NOX1 peptide inhibitor.
To analyze the contribution of NOX1 on tumorigenic transformation, we are now investigating whether NOX1 ablation (both genetically and chemically) can affect UVB-induced photoaging and tumoral transformation of keratinocytes. We will also investigate the role of NOX1 in physiological skin aging.
This basic science project is closely associated with a translational part which will test, with the help of the Fondation Maladies Rares and the Patient’s support group “Les Enfants de la Lune”, a clinical grade lotion of the patented NOX-1 inhibitor.
- NADPH oxidases and their roles in skin homeostasis and carcinogenesis. Rudolf J, Raad H, Taieb A, Rezvani HR. Antioxid Redox Signal () 2018 28(13):1238-1261. PMID: 289
- Diagnosis of Xeroderma pigmentosum variant in a young patient with two novel mutations in the POLH gene. De Palma A, Morren MA, Ged C, Pouvelle C, Taïeb A, Aoufouchi S, Sarasin A. Am J Med Genet A. () PMID: 28688171
- NADPH oxidase-1 plays a key role in keratinocyte responses to ultraviolet radiation and UVB-induced skin carcinogenesis. Raad H, Serrano-Sanchez M, Harfouche G, Mahfouf W, Bortolotto D, Bergeron V, Kasraian Z, Hosseini M, Taieb A, Rezvani HR. J Invest Dermatol () 2017, 137(6):1311-1321.
- Premature skin aging features rescued by inhibition of NADPH oxidase activity in XPC-deficient mice. Hosseini M, Mahfouf W, Serrano-Sanchez M, Raad H, Harfouche G, Bonneu M, Claverol S, Mazurier F, Rossignol R, Taieb A, Rezvani HR. J Invest Dermatol. () 135(4):1108-18
- Oxidative and energy metabolism as potential clues for clinical heterogeneity in nucleotide excision repair disorders. Hosseini M, Ezzedine K, Taieb A, Rezvani HR. J Invest Dermatol. () 135(2):341-51
- Inhibition of p38 MAPK signaling augments skin tumorigenesis via NOX2 driven ROS generation. Liu L, Rezvani HR, Back JH, Hosseini M, Tang X, Zhu Y, Mahfouf W, Raad H, Raji G, Athar M, Kim AL, Bickers DR. PLoS One. () 9(5):e97245
- XPC silencing in normal human keratinocytes triggers metabolic alterations through NOX-1 activation-mediated reactive oxygen species. Rezvani HR, Rossignol R, Ali N, Benard G, Tang X, Yang HS, Jouary T, deVerneuil H, Taïeb A, Kim AL, Mazurier F. Biochim Biop () 1807(6):609-19
- XPC silencing in normal human keratinocytes triggers metabolic alterations that drive the formation of squamous cell carcinomas. Rezvani HR, Kim AL, Rossignol R, Ali N, Daly M, Mahfouf W, Bellance N, Taïeb A, de Verneuil H, Mazurier F, Bickers DR. J Clin Invest. () 121(1):195-211
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