Selective induction of apoptosis by leptomycin B in keratinocytes expressing HPV oncogenes

Lindsey J. Gray, Predrag Bjelogrlic, Virginia C. L. Appleyard, Alastair M. Thompson, Carol E. Jolly, Sonia Lain, C. Simon Herrington

    Research output: Contribution to journalArticle

    19 Citations (Scopus)

    Abstract

    Human papillomavirus (HPV) infection is strongly associated with the development of anogenital neoplasia, particularly cervical cancer. It has been estimated that 99.7% of all cervical carcinomas are attributable to infection with HPV, and types 16 and 18 account for the vast majority of such cases. Both of these 'high risk' HPV types encode the oncoproteins E6 and E7, which exert multiple effects on many proteins involved in cell-cycle regulation, including p53. The nuclear export protein inhibitor leptomycin B (LMB) has been shown to cause the nuclear sequestration of p53 in cervical carcinoma cells. We demonstrate that LMB induces apoptosis selectively at nanomolar concentrations in primary human keratinocytes (PHKs) expressing HPV oncogenes. Both monolayer and organotypic raft cultures of transduced PHKs were highly susceptible to treatment with LMB. By contrast, although LMB stimulated p53 accumulation in normal PHKs, no significant induction of apoptosis was detected on Western blots or immunostained monolayer/raft cells, or following pulsed exposure to the drug. Furthermore, topical application of mu M concentrations of LMB to mouse skin was non-toxic. These data suggest that the topical application of LMB to HPV-infected intra-epithelial lesions may represent a specific and effective therapeutic strategy against HPV-associated anogenital neoplasia. (c) 2007 Wiley-Liss, Inc.

    Original languageEnglish
    Pages (from-to)2317-2324
    Number of pages8
    JournalInternational Journal of Cancer
    Volume120
    Issue number11
    Early online date8 Feb 2007
    DOIs
    Publication statusPublished - 1 Jun 2007

    Keywords

    • Human papillomavirus
    • Leptomycin B
    • Keratinocytes
    • Oncogenes
    • Apoptosis

    Cite this

    Gray, L. J., Bjelogrlic, P., Appleyard, V. C. L., Thompson, A. M., Jolly, C. E., Lain, S., & Herrington, C. S. (2007). Selective induction of apoptosis by leptomycin B in keratinocytes expressing HPV oncogenes. International Journal of Cancer, 120(11), 2317-2324. https://doi.org/10.1002/ijc.22591
    Gray, Lindsey J. ; Bjelogrlic, Predrag ; Appleyard, Virginia C. L. ; Thompson, Alastair M. ; Jolly, Carol E. ; Lain, Sonia ; Herrington, C. Simon. / Selective induction of apoptosis by leptomycin B in keratinocytes expressing HPV oncogenes. In: International Journal of Cancer. 2007 ; Vol. 120, No. 11. pp. 2317-2324.
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    abstract = "Human papillomavirus (HPV) infection is strongly associated with the development of anogenital neoplasia, particularly cervical cancer. It has been estimated that 99.7{\%} of all cervical carcinomas are attributable to infection with HPV, and types 16 and 18 account for the vast majority of such cases. Both of these 'high risk' HPV types encode the oncoproteins E6 and E7, which exert multiple effects on many proteins involved in cell-cycle regulation, including p53. The nuclear export protein inhibitor leptomycin B (LMB) has been shown to cause the nuclear sequestration of p53 in cervical carcinoma cells. We demonstrate that LMB induces apoptosis selectively at nanomolar concentrations in primary human keratinocytes (PHKs) expressing HPV oncogenes. Both monolayer and organotypic raft cultures of transduced PHKs were highly susceptible to treatment with LMB. By contrast, although LMB stimulated p53 accumulation in normal PHKs, no significant induction of apoptosis was detected on Western blots or immunostained monolayer/raft cells, or following pulsed exposure to the drug. Furthermore, topical application of mu M concentrations of LMB to mouse skin was non-toxic. These data suggest that the topical application of LMB to HPV-infected intra-epithelial lesions may represent a specific and effective therapeutic strategy against HPV-associated anogenital neoplasia. (c) 2007 Wiley-Liss, Inc.",
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    Gray, LJ, Bjelogrlic, P, Appleyard, VCL, Thompson, AM, Jolly, CE, Lain, S & Herrington, CS 2007, 'Selective induction of apoptosis by leptomycin B in keratinocytes expressing HPV oncogenes', International Journal of Cancer, vol. 120, no. 11, pp. 2317-2324. https://doi.org/10.1002/ijc.22591

    Selective induction of apoptosis by leptomycin B in keratinocytes expressing HPV oncogenes. / Gray, Lindsey J.; Bjelogrlic, Predrag; Appleyard, Virginia C. L.; Thompson, Alastair M.; Jolly, Carol E.; Lain, Sonia; Herrington, C. Simon.

    In: International Journal of Cancer, Vol. 120, No. 11, 01.06.2007, p. 2317-2324.

    Research output: Contribution to journalArticle

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    AU - Gray, Lindsey J.

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    AB - Human papillomavirus (HPV) infection is strongly associated with the development of anogenital neoplasia, particularly cervical cancer. It has been estimated that 99.7% of all cervical carcinomas are attributable to infection with HPV, and types 16 and 18 account for the vast majority of such cases. Both of these 'high risk' HPV types encode the oncoproteins E6 and E7, which exert multiple effects on many proteins involved in cell-cycle regulation, including p53. The nuclear export protein inhibitor leptomycin B (LMB) has been shown to cause the nuclear sequestration of p53 in cervical carcinoma cells. We demonstrate that LMB induces apoptosis selectively at nanomolar concentrations in primary human keratinocytes (PHKs) expressing HPV oncogenes. Both monolayer and organotypic raft cultures of transduced PHKs were highly susceptible to treatment with LMB. By contrast, although LMB stimulated p53 accumulation in normal PHKs, no significant induction of apoptosis was detected on Western blots or immunostained monolayer/raft cells, or following pulsed exposure to the drug. Furthermore, topical application of mu M concentrations of LMB to mouse skin was non-toxic. These data suggest that the topical application of LMB to HPV-infected intra-epithelial lesions may represent a specific and effective therapeutic strategy against HPV-associated anogenital neoplasia. (c) 2007 Wiley-Liss, Inc.

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    Gray LJ, Bjelogrlic P, Appleyard VCL, Thompson AM, Jolly CE, Lain S et al. Selective induction of apoptosis by leptomycin B in keratinocytes expressing HPV oncogenes. International Journal of Cancer. 2007 Jun 1;120(11):2317-2324. https://doi.org/10.1002/ijc.22591