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 journalArticlepeer-review

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 microM 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.

Original languageEnglish
Pages (from-to)2317-24
Number of pages8
JournalInternational Journal of Cancer
Volume120
Issue number11
DOIs
Publication statusPublished - 1 Jun 2007

Keywords

  • Apoptosis
  • Blotting, Western
  • Cells, Cultured
  • Fatty Acids, Unsaturated
  • Humans
  • Immunohistochemistry
  • Keratinocytes
  • Oncogenes
  • Papillomaviridae

Fingerprint Dive into the research topics of 'Selective induction of apoptosis by leptomycin B in keratinocytes expressing HPV oncogenes'. Together they form a unique fingerprint.

Cite this