Syringic acid prevents skin carcinogenesis via regulation of NoX and EGFR signaling

Biochem Pharmacol. 2018 Aug:154:435-445. doi: 10.1016/j.bcp.2018.06.007. Epub 2018 Jun 7.

Abstract

Validation of nutraceutical and pharmaceutical targets is essential for the prediction of physiological and side effects. Epidemiologic evidence and molecular studies suggest that non-melanoma skin cancer is directly associated with excessive exposure to ultraviolet (UV) radiation. The aim of the present study was to evaluate the inhibitory effects of syringic acid on UVB-induced signaling and skin carcinogenesis, and determine the molecular targets. Treatment of human epidermal keratinocytes (HaCaT) cells with syringic acid resulted in the suppression of UVB-induced cyclooxygenase-2, matrix metalloproteinase-1, and prostaglandin E2 expression as well as activator protein-1 activity. Moreover, syringic acid inhibited the UVB-induced phosphorylation of mitogen-activated protein kinases and Akt signaling pathways as well as epidermal growth factor receptor (EGFR). Syringic acid treatment further inhibited intracellular reactive oxygen species and protein-tyrosine phosphatase-κ activity, a regulator of EGFR activation. Syringic acid and the antioxidant N-acetyl-l-cysteine inhibited UVB-induced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. In vivo, pretreatment of mouse skin with syringic acid significantly suppressed UVB-induced skin tumor incidence in a dose-dependent manner. Overall, these results indicate that syringic acid exerts potent chemopreventive activity in skin carcinogenesis mainly by inhibition of the Nox/PTP-κ/EGFR axis. Syringic acid might serve as an effective chemopreventive and therapeutic agent against UVB-mediated skin cancer.

Keywords: Cyclooxygenase-2; Epidermal growth factor receptor; Matrix metalloproteinase-1; Protein-tyrosine phosphatase-κ; Reactive oxygen species; Skin cancer; Syringic acid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Dose-Response Relationship, Drug
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / metabolism
  • Gallic Acid / analogs & derivatives*
  • Gallic Acid / pharmacology
  • Gallic Acid / therapeutic use
  • Humans
  • Keratinocytes / drug effects
  • Keratinocytes / metabolism
  • Keratinocytes / radiation effects
  • Male
  • Mice
  • Mice, Hairless
  • NADPH Oxidases / antagonists & inhibitors*
  • NADPH Oxidases / metabolism
  • Signal Transduction / drug effects*
  • Signal Transduction / physiology
  • Skin Neoplasms / etiology
  • Skin Neoplasms / metabolism
  • Skin Neoplasms / prevention & control*
  • Ultraviolet Rays / adverse effects

Substances

  • Gallic Acid
  • syringic acid
  • NADPH Oxidases
  • EGFR protein, human
  • ErbB Receptors