Uncovering novel targets for cancer chemoprevention.

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.