Harnessing the gatekeepers of glucocorticoids for chemoprevention of non-melanoma skin cancer

Anna M. Mancha-Ramirez, Xiaoyu Yang, Huiyun Liang, Jacob Junco, Kevin P. Lee, Sarah F. Bovio, Maricruz Espinoza, Julia Wool, Andrew Slaga, Daniel C. Glade, Martha Hanes, Gunjan Malik, Dae Joon Kim, John DiGiovanni, Thomas J. Slaga

Research output: Contribution to journalArticle

Abstract

Despite effective surgical methods for non-melanoma skin cancer (NMSC), patients suffer from tissue damage, scarring, or even disfigurement; thus, there is a need for chemopreventive approaches. Because of the complex interplay between glucocorticoids (GCs), inflammation, and cancer, we sought to determine the role of 11β-hydroxysteroid dehydrogenase 1 and 2 (11βHSD1 and 2) in regulating GCs during skin cancer development and progression. 11βHSDs modulate the activation of GCs in a tissue-specific manner and have been reported to play a role in development and progression of other types of cancer, but their role has not yet been reported in NMSC. Here, we found a significant upregulation of 11βHSD2 protein in skin cancer cells when compared to normal skin cells, suggesting a role for this enzyme in the multifactorial process of skin cancer development. In addition, inhibition of 11βHSD2 with siRNA resulted in significant reduction in colony formation in vitro. Finally, our in vivo study elucidated that inhibition of 11βHSD2 with pharmacological inhibitor, Glycyrrhetinic acid (GA) could significantly diminish tumorigenesis in a well-studied in vivo mouse model of NMSC. Overall, these studies highlight for the first time a potential novel role for 11βHSD2 in NMSC development and may allow for new GC treatment approaches capable of avoiding deactivation by the enzyme. If 11βHSD2 can be inhibited as we have done here, or circumvented using modified GCs, this may lead to more efficacious outcomes for NMSC patients by preventing deactivation of the GC and minimizing resistance.

Original languageEnglish (US)
Pages (from-to)102-112
Number of pages11
JournalMolecular Carcinogenesis
Volume58
Issue number1
DOIs
StatePublished - Jan 2019

Keywords

  • 11β-hydroxysteroid dehydrogenases
  • chemoprevention
  • glucocorticoids
  • glycyrrhetinic acid
  • non-melanoma skin cancer
  • phytochemicals

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

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  • Cite this

    Mancha-Ramirez, A. M., Yang, X., Liang, H., Junco, J., Lee, K. P., Bovio, S. F., Espinoza, M., Wool, J., Slaga, A., Glade, D. C., Hanes, M., Malik, G., Kim, D. J., DiGiovanni, J., & Slaga, T. J. (2019). Harnessing the gatekeepers of glucocorticoids for chemoprevention of non-melanoma skin cancer. Molecular Carcinogenesis, 58(1), 102-112. https://doi.org/10.1002/mc.22912