Selective induction of apoptosis by leptomycin B in keratinocytes expressing HPV oncogenes
Article first published online: 8 FEB 2007
Copyright © 2007 Wiley-Liss, Inc.
International Journal of Cancer
Volume 120, Issue 11, pages 2317–2324, 1 June 2007
How to Cite
Gray, L. J., Bjelogrlic, P., Appleyard, V. C.L., Thompson, A. M., Jolly, C. E., Lain, S. and Herrington, C. S. (2007), Selective induction of apoptosis by leptomycin B in keratinocytes expressing HPV oncogenes. Int. J. Cancer, 120: 2317–2324. doi: 10.1002/ijc.22591
- Issue published online: 27 MAR 2007
- Article first published online: 8 FEB 2007
- Manuscript Accepted: 6 DEC 2006
- Manuscript Received: 26 MAY 2006
- Cancer Research UK. Grant Number: C8/A1449
- University of St. Andrews, Breast Cancer Research Scotland
- human papillomavirus;
- leptomycin B;
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 μM 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. © 2007 Wiley-Liss, Inc.