Uncovering novel targets for cancer chemoprevention.

Konstantin H. Dragnev, Qing Feng, Yan Ma, Sumit J. Shah, Candice Black, Vincent Memoli, William Nugent, James R. Rigas, Sutisak Kitareewan, Sarah Freemantle, Ethan Dmitrovsky

Research output: Contribution to journalReview article

Abstract

Tobacco carcinogen treatment of immortalized human bronchial epithelial (HBE) cells has uncovered novel targets for cancer chemoprevention. Experiments were conducted with HBE cells and independent treatments with tobacco carcinogens along with the chemopreventive agent all-trans-retinoic acid (RA). That work highlighted D-type and E-type cyclins as novel molecular pharmacologic targets of several chemopreventive agents. G1 cyclins are often aberrantly expressed in bronchial preneoplasia and lung cancers. This implicated these species as targets for clinical cancer chemoprevention. Retinoid regulation mechanisms of D-type cyclins in lung cancer chemoprevention have been comprehensively explored. Retinoid chemoprevention has been mechanistically linked to proteasomal degradation of cyclin D1 and cyclin D3. Threonine 286 mutation stabilized cyclin D1, implicating phosphorylation in this retinoid chemoprevention. Studies with a phospho-specific anti-cyclin D1 antibody confirmed this hypothesis. Glycogen synthase kinase (GSK) inhibitors established a role for this kinase in the retinoid regulation of cyclin D1, but not cyclin D3. Involvement of D-type cyclins in this chemoprevention was shown using small interfering RNAs (siRNAs). Gene profiling experiments highlighted the E1-like ubiquitin-activating enzyme (UBE1L) in the retinoid regulation of cyclin D1. Proof of principle trials have translated these studies into the clinic and established that chemopreventive agents can target D-type cyclins. These findings have been built upon with a targeted combination regimen that cooperatively affects D-type cyclins. Taken together, these preclinical and clinical findings strongly implicate these cyclins as novel molecular pharmacological targets for cancer chemoprevention.

Original languageEnglish (US)
Pages (from-to)235-243
Number of pages9
JournalRecent results in cancer research. Fortschritte der Krebsforschung. Progrès dans les recherches sur le cancer
Volume174
StatePublished - 2007
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Dragnev, K. H., Feng, Q., Ma, Y., Shah, S. J., Black, C., Memoli, V., Nugent, W., Rigas, J. R., Kitareewan, S., Freemantle, S., & Dmitrovsky, E. (2007). Uncovering novel targets for cancer chemoprevention. Recent results in cancer research. Fortschritte der Krebsforschung. Progrès dans les recherches sur le cancer, 174, 235-243.