EGFR-Mediated Akt and MAPKs Signal Pathways Play a Crucial Role in Patulin-Induced Cell Proliferation in Primary Murine Keratinocytes via Modulation of Cyclin D1 and COX-2 Expression

Patulin (PAT), a present day major contaminant of commercial apple and apple products is reported to be carcinogenic, embryotoxic, and immunotoxic. While oral and inhalation are considered to be the most prevalent routes of exposure to this toxin, exposure through skin is now being extensively investigated. Our previous study showed that short-term dermal exposure to PAT resulted in toxicological injury to the skin, while long-term exposure induced skin tumorigenesis. In this study, we explore the mechanism involve in proliferation of mouse keratinocytes by PAT. Our study revealed that PAT rapidly induces phosphorylation of EGFR, activation of the Ras/MAPKs, and Akt pathways. This in-turn leads to the activation of NF-B/AP-1 transcription factors which then binds to the promoter region of the cell growth regulatory genes Cyclin D1 and COX-2 inducing their expression leading ultimately to PMKs proliferation. Inhibition of EGFR or the Ras/MAPKs, PI3/Akt pathways with different pharmacological inhibitors or knockdown of NF-B, c-jun, c-fos, Cyclin D1, and COX-2 with siRNA inhibited PAT-induced PMKs proliferation. (c) 2013 Wiley Periodicals, Inc.