title: Effect of deguelin on UVB-induced skin carcinogenesis.
abstract: Nonmelanoma skin cancer afflicts more than one million people in the U.S. annually, highlighting the need for more effective preventive regimens. We have investigated the ability of deguelin, a plant-derived rotenoid with cancer chemopreventive activity, to inhibit UVB-induced skin carcinogenesis with the SKh-1 mouse model. Topically-applied deguelin significantly inhibited the multiplicity of UVB-induced skin tumors, indicating potential as a human skin cancer chemopreventive agent. Mechanistic studies to determine the potential of deguelin to block a number of established UVB-induced molecular events yielded negative results [including UVB-induced AP-1 DNA binding, c-fos and TNFalpha mRNA induction, arachidonic acid release and UVB-induced phosphorylation of mTOR (Ser2448), akt (Ser473) and erk (Thr202/Tyr204)]. These results are of interest as they contradict a major hypothesis for the mode of action of deguelin, i.e., a general down regulation of signal transduction based on inhibition of NADH dehydrogenase and depletion of ATP levels. In the current work, however, deguelin was found to activate 5' AMP-activated kinase (AMPK), a protein that acts as a cellular energy sensor. This is the first report of a chemopreventive agent having this effect and suggests a possible role for AMPK in cancer chemoprevention.
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Gills
authors.forename: J
authors.initials: J
authors.lastname: Kosmeder
authors.forename: R C
authors.initials: RC
authors.lastname: Moon
authors.forename: D D
authors.initials: DD
authors.lastname: Lantvit
authors.forename: J M
authors.initials: JM
authors.lastname: Pezzuto
mesh_terms: D055372:AMP-Activated Protein Kinases; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D018890:Chemoprevention; D018736:DNA Adducts; D015536:Down-Regulation; D005260:Female; D006801:Humans; D051379:Mice; D009097:Multienzyme Complexes / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012402:Rotenone / Q000031:analogs & derivatives* / Q000494:pharmacology; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000209:etiology / Q000517:prevention & control*; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays / Q000009:adverse effects*
chemical_list: D018736:DNA Adducts; D009097:Multienzyme Complexes; D012402:Rotenone; D000255:Adenosine Triphosphate; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C107676:deguelin