title: Inactivation of glutathione peroxidase activity contributes to UV-induced squamous cell carcinoma formation.
abstract: Cutaneous squamous cell carcinomas (CSCC) are a common malignancy of keratinocytes that arise in sites of the skin exposed to excessive UV radiation. In the present study, we show that human SCC cell lines, preneoplastic solar keratoses (SK), and CSCC are associated with perturbations in glutathione peroxidase (GPX) activity and peroxide levels. Specifically, we found that two of three SKs and four of five CSCCs, in vivo, were associated with decreased GPX activity and all SKs and CSCCs were associated with an elevated peroxide burden. Given the association of decreased GPX activity with CSCC, we examined the basis for the GPX deficiency in the CSCCs. Our data indicated that GPX was inactivated by a post-translational mechanism and that GPX could be inactivated by increases in intracellular peroxide levels. We next tested whether the decreased peroxidase activity coupled with an elevated peroxidative burden might contribute to CSCC formation in vivo. This was tested in Gpx1(-/-) and Gpx2(-/-) mice exposed to solar-simulated UV radiation. These studies showed that Gpx2 deficiency predisposed mice to UV-induced CSCC formation. These results suggest that inactivation of GPX2 in human skin may be an early event in UV-induced SCC formation.
authors.affiliation: Epithelial Pathobiology Group, Cancer Biology Programme, Diamantina Institute for Cancer, Immunology and Metabolic Medicine, University of Queensland, Queensland, Australia.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Walshe
authors.forename: Magdalena M
authors.initials: MM
authors.lastname: Serewko-Auret
authors.forename: Ngari
authors.initials: N
authors.lastname: Teakle
authors.forename: Sarina
authors.initials: S
authors.lastname: Cameron
authors.forename: Kelly
authors.initials: K
authors.lastname: Minto
authors.forename: Louise
authors.initials: L
authors.lastname: Smith
authors.forename: Philip C
authors.initials: PC
authors.lastname: Burcham
authors.forename: Terry
authors.initials: T
authors.lastname: Russell
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Strutton
authors.forename: Anthony
authors.initials: A
authors.lastname: Griffin
authors.forename: Fong-Fong
authors.initials: FF
authors.lastname: Chu
authors.forename: Stephen
authors.initials: S
authors.lastname: Esworthy
authors.forename: Vivienne
authors.initials: V
authors.lastname: Reeve
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Saunders
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000209:etiology*; D004789:Enzyme Activation; D005979:Glutathione Peroxidase / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D015603:Keratinocytes / Q000201:enzymology / Q000473:pathology / Q000528:radiation effects; D009381:Neoplasms, Radiation-Induced / Q000201:enzymology* / Q000209:etiology; D010545:Peroxides / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012878:Skin Neoplasms / Q000201:enzymology* / Q000209:etiology*; D014466:Ultraviolet Rays
chemical_list: D007527:Isoenzymes; D010545:Peroxides; D012333:RNA, Messenger; C117436:GPX2 protein, human; D005979:Glutathione Peroxidase