Inactivation of Glutathione Peroxidase Activity Contributes to UV-Induced Squamous Cell Carcinoma Formation

J. Walshe, M.M. Serewko-Auret, N. Teakle, S. Cameron, K. Minto, L. Smith, Philip Burcham, T. Russell, G. Strutton, A. Griffin, F.F. Chu, S. Esworthy, V. Reeve, N.A. Saunders

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    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 he an early event in UV-induced SCC formation.
    Original languageEnglish
    Pages (from-to)4751-4758
    JournalCancer Research
    Volume67
    Issue number10
    DOIs
    Publication statusPublished - 2007

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    Glutathione Peroxidase
    Squamous Cell Carcinoma
    Skin
    Peroxides
    Radiation
    Keratosis
    Keratinocytes
    Peroxidase
    Cell Line
    Neoplasms

    Cite this

    Walshe, J., Serewko-Auret, M. M., Teakle, N., Cameron, S., Minto, K., Smith, L., ... Saunders, N. A. (2007). Inactivation of Glutathione Peroxidase Activity Contributes to UV-Induced Squamous Cell Carcinoma Formation. Cancer Research, 67(10), 4751-4758. https://doi.org/10.1158/0008-5472.CAN-06-4192
    Walshe, J. ; Serewko-Auret, M.M. ; Teakle, N. ; Cameron, S. ; Minto, K. ; Smith, L. ; Burcham, Philip ; Russell, T. ; Strutton, G. ; Griffin, A. ; Chu, F.F. ; Esworthy, S. ; Reeve, V. ; Saunders, N.A. / Inactivation of Glutathione Peroxidase Activity Contributes to UV-Induced Squamous Cell Carcinoma Formation. In: Cancer Research. 2007 ; Vol. 67, No. 10. pp. 4751-4758.
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    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 he an early event in UV-induced SCC formation.",
    author = "J. Walshe and M.M. Serewko-Auret and N. Teakle and S. Cameron and K. Minto and L. Smith and Philip Burcham and T. Russell and G. Strutton and A. Griffin and F.F. Chu and S. Esworthy and V. Reeve and N.A. Saunders",
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    Walshe, J, Serewko-Auret, MM, Teakle, N, Cameron, S, Minto, K, Smith, L, Burcham, P, Russell, T, Strutton, G, Griffin, A, Chu, FF, Esworthy, S, Reeve, V & Saunders, NA 2007, 'Inactivation of Glutathione Peroxidase Activity Contributes to UV-Induced Squamous Cell Carcinoma Formation' Cancer Research, vol. 67, no. 10, pp. 4751-4758. https://doi.org/10.1158/0008-5472.CAN-06-4192

    Inactivation of Glutathione Peroxidase Activity Contributes to UV-Induced Squamous Cell Carcinoma Formation. / Walshe, J.; Serewko-Auret, M.M.; Teakle, N.; Cameron, S.; Minto, K.; Smith, L.; Burcham, Philip; Russell, T.; Strutton, G.; Griffin, A.; Chu, F.F.; Esworthy, S.; Reeve, V.; Saunders, N.A.

    In: Cancer Research, Vol. 67, No. 10, 2007, p. 4751-4758.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Inactivation of Glutathione Peroxidase Activity Contributes to UV-Induced Squamous Cell Carcinoma Formation

    AU - Walshe, J.

    AU - Serewko-Auret, M.M.

    AU - Teakle, N.

    AU - Cameron, S.

    AU - Minto, K.

    AU - Smith, L.

    AU - Burcham, Philip

    AU - Russell, T.

    AU - Strutton, G.

    AU - Griffin, A.

    AU - Chu, F.F.

    AU - Esworthy, S.

    AU - Reeve, V.

    AU - Saunders, N.A.

    PY - 2007

    Y1 - 2007

    N2 - 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 he an early event in UV-induced SCC formation.

    AB - 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 he an early event in UV-induced SCC formation.

    U2 - 10.1158/0008-5472.CAN-06-4192

    DO - 10.1158/0008-5472.CAN-06-4192

    M3 - Article

    VL - 67

    SP - 4751

    EP - 4758

    JO - Cancer Research

    JF - Cancer Research

    SN - 0008-5472

    IS - 10

    ER -