title: Quercetin potentiates UVB-Induced c-Fos expression: implications for its use as a chemopreventive agent.
abstract: Quercetin (Qu) is currently being investigated as a chemopreventive agent for several cancers, including nonmelanoma skin cancer induced by UV light. We previously reported that Qu degradation has important consequences on signaling and cell biology. In the current study, we report that Qu induces c-Fos mRNA and protein expression through activation of p38 and cAMP-responsive element binding protein (CREB), and Qu potentiates UVB-induced c-Fos expression. Inclusion of ascorbic acid (AA) in cell culture medium stabilizes Qu and completely prevents both Qu- and UVB-induced p38 and CREB activation, leading to a blockade of c-fos gene expression through reduced CREB/cAMP-responsive element binding. AA stabilizes c-Fos mRNA, increasing steady-state levels even when c-fos gene expression is suppressed, but this has no effect on c-Fos protein levels in either mock- or UVB-irradiated cells. We report that Qu blocks mammalian target of rapamycin signaling and inhibits c-Fos protein expression directly through this mechanism because cotreatment with Qu and AA resulted in the complete suppression of UVB-induced c-Fos protein expression even in the presence of significantly increased mRNA levels. We further confirmed that this was not due to increased protein turnover because inhibition of proteasome activity with MG-132 did not raise c-Fos protein levels in Qu+AA-treated cells. Together, these data indicate that although Qu has been reported to have some beneficial properties as a chemopreventive agent, it is also capable of inducing c-fos expression, a cellular event important for the promotion phase of tumor development, if it is not stabilized.
authors.affiliation: Arizona Cancer Center, University of Arizona, Tucson, USA. eolson@azcc.arizona.edu
authors.forename: Erik R
authors.initials: ER
authors.lastname: Olson
authors.forename: Tania
authors.initials: T
authors.lastname: Melton
authors.forename: Sally E
authors.initials: SE
authors.lastname: Dickinson
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
authors.forename: David S
authors.initials: DS
authors.lastname: Alberts
authors.forename: G Tim
authors.initials: GT
authors.lastname: Bowden
mesh_terms: D016588:Anticarcinogenic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001205:Ascorbic Acid / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004355:Drug Stability; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D011794:Quercetin / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D012878:Skin Neoplasms / Q000517:prevention & control; D058570:TOR Serine-Threonine Kinases; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D016588:Anticarcinogenic Agents; D017362:Cyclic AMP Response Element-Binding Protein; D047908:Intracellular Signaling Peptides and Proteins; D016760:Proto-Oncogene Proteins c-fos; D011794:Quercetin; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D001205:Ascorbic Acid