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Research Articles: Targets

Silibinin inhibits UVB- and epidermal growth factor–induced mitogenic and cell survival signaling involving activator protein-1 and nuclear factor-B in mouse epidermal JB6 cells

¹ Department of Pharmaceutical Sciences, School of Pharmacy and ² University of Colorado Cancer Center, University of Colorado Health Sciences Center, Denver, Colorado

Requests for reprints: Rajesh Agarwal, Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Box C238, Denver, CO 80262. Phone: 303-315-1381; Fax: 303-315-6281. E-mail: Rajesh.Agarwal{at}uchsc.edu

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/cm²) dose-dependently induced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun-NH₂-kinase 1/2 (JNK1/2), and p38 kinase (p38K) as well as Akt, with an optimum response at 400 mJ/cm² 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-B (NF-B) 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-B activation. Because AP-1 and NF-B 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-B. [Mol Cancer Ther 2006;5(5):1145–53]

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Received 11/18/05; revised 2/22/06; accepted 3/17/06.