Inactivation of glutathione peroxidase activity contributes to UV-induced squamous cell carcinoma formation.
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.
Walshe
Jennifer
J
Epithelial Pathobiology Group, Cancer Biology Programme, Diamantina Institute for Cancer, Immunology and Metabolic Medicine, University of Queensland, Queensland, Australia.
Serewko-Auret
Magdalena M
MM
Teakle
Ngari
N
Cameron
Sarina
S
Minto
Kelly
K
Smith
Louise
L
Burcham
Philip C
PC
Russell
Terry
T
Strutton
Geoffrey
G
Griffin
Anthony
A
Chu
Fong-Fong
FF
Esworthy
Stephen
S
Reeve
Vivienne
V
Saunders
Nicholas A
NA
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
D007527:Isoenzymes; D010545:Peroxides; D012333:RNA, Messenger; C117436:GPX2 protein, human; D005979:Glutathione Peroxidase