title: Silibinin inhibits UVB- and epidermal growth factor-induced mitogenic and cell survival signaling involving activator protein-1 and nuclear factor-kappaB in mouse epidermal JB6 cells.
abstract: UVB radiation is the major etiologic factor in the development of nonmelanoma skin cancer. In addition to tumor-initiating effect, UVB also causes tumor promotion via mitogenic and survival signaling. Studies have shown strong preventive effects of silibinin against both UVB-induced and chemically induced tumor promotion in mouse skin models; however, mechanisms are not understood completely. Here, we used tumor promoter-sensitive JB6 mouse epithelial cell model and studied the effect of silibinin on two different mitogens [UVB and epidermal growth factor (EGF)] that induce mitogenic and cell survival signaling pathways. UVB (50-800 mJ/cm(2)) dose-dependently induced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun-NH(2)-kinase 1/2 (JNK1/2), and p38 kinase (p38K) as well as Akt, with an optimum response at 400 mJ/cm(2) UVB dose. UVB caused a biphasic phosphorylation of ERK1/2 in a time kinetics study. Silibinin treatment before or immediately after UVB exposure, or both, resulted in a strong decrease in UVB-caused phosphorylation of ERK1/2 and Akt in both dose- and time-dependent manner, without any substantial response on JNK1/2 and p38K. Silibinin also suppressed UVB-induced activator protein-1 (AP-1) and nuclear factor-kappaB (NF-kappaB) activation, which are activated by ERK1/2 and Akt. Silibinin treatment under similar conditions also strongly inhibited EGF-induced ERK1/2, JNK1/2, and p38K as well as Akt phosphorylation, and also suppressed EGF-induced AP-1 and NF-kappaB activation. Because AP-1 and NF-kappaB are important nuclear transcription factors for tumor promotion, these results suggest that silibinin possibly prevents skin tumor promotion by inhibiting UVB- and EGF-induced mitogenic and cell survival signaling involving both AP-1 and NF-kappaB.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Box C238, Denver, CO 80262, USA.
authors.forename: Rana P
authors.initials: RP
authors.lastname: Singh
authors.forename: Sivanandhan
authors.initials: S
authors.lastname: Dhanalakshmi
authors.forename: Sarumathi
authors.initials: S
authors.lastname: Mohan
authors.forename: Chapla
authors.initials: C
authors.lastname: Agarwal
authors.forename: Rajesh
authors.initials: R
authors.lastname: Agarwal
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D000078404:Epidermal Cells; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D004817:Epidermis / Q000187:drug effects / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000528:radiation effects; D051379:Mice; D008938:Mitosis / Q000187:drug effects / Q000528:radiation effects; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D000077385:Silybin; D012838:Silymarin / Q000378:metabolism / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014466:Ultraviolet Rays / Q000009:adverse effects
chemical_list: D000975:Antioxidants; D016328:NF-kappa B; D012838:Silymarin; D018808:Transcription Factor AP-1; D000077385:Silybin; D004815:Epidermal Growth Factor; D051057:Proto-Oncogene Proteins c-akt