Protective role of cathepsin L in mouse skin carcinogenesis

Fernando Benavides, Carlos Perez, Jorge Blando, Oscar Contreras, Jianjun Shen, Lisa M. Coussens, Susan M. Fischer, Donna F. Kusewitt, John Digiovanni, Claudio J. Conti

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Lysosomal cysteine protease cathepsin L (CTSL) is believed to play a role in tumor progression and is considered a marker for clinically invasive tumors. Studies from our laboratory using the classical mouse skin carcinogenesis model, with 7,12-dimethyl-benz[a]anthracene (DMBA) for initiation and 12-O-tetradecanoylphorbol-13-acetate (TPA) for promotion, showed that expression of CTSL is increased in papillomas and squamous cell carcinomas (SCC). We also carried out carcinogenesis studies using Ctsl-deficient nackt (nkt) mutant mice on three different inbred backgrounds. Unexpectedly, the multiplicity of papillomas was significantly higher in Ctsl-deficient than in wild-type mice on two unrelated backgrounds. Topical applications of TPA or DMBA alone to the skin of nkt/nkt mice did not induce papillomas, and there was no increase in spontaneous tumors in nkt/nkt mice on any of the three inbred backgrounds. Reduced epidermal cell proliferation in Ctsl-deficient nkt/nkt mice after TPA treatment suggested that they are not more sensitive than wild-type mice to TPA promotion. We also showed that deficiency of CTSL delays terminal differentiation of keratinocytes, and we propose that decreased elimination of initiated cells is at least partially responsible for the increased papilloma formation in the nackt model.

Original languageEnglish (US)
Pages (from-to)352-361
Number of pages10
JournalMolecular Carcinogenesis
Volume51
Issue number4
DOIs
StatePublished - Apr 2012

Keywords

  • Cysteine cathepsins
  • Mouse models
  • Proteases
  • Skin cancer
  • Two-stage carcinogenesis

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

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  • Cite this

    Benavides, F., Perez, C., Blando, J., Contreras, O., Shen, J., Coussens, L. M., Fischer, S. M., Kusewitt, D. F., Digiovanni, J., & Conti, C. J. (2012). Protective role of cathepsin L in mouse skin carcinogenesis. Molecular Carcinogenesis, 51(4), 352-361. https://doi.org/10.1002/mc.20792