Effect of deguelin on UVB-induced skin carcinogenesis.
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.
Gills
J J
JJ
Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, IL 60612, USA.
Kosmeder
J
J
Moon
R C
RC
Lantvit
D D
DD
Pezzuto
J M
JM
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*
D018736:DNA Adducts; D009097:Multienzyme Complexes; D012402:Rotenone; D000255:Adenosine Triphosphate; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C107676:deguelin