Piperonylic acid stimulates keratinocyte growth and survival by activating epidermal growth factor receptor (EGFR)

Abstract

Epidermal growth factor (EGF) stimulates cell growth, proliferation, and survival. The biological benefits of EGF have been utilized in medical uses for improving wound healing as well as in today’s skin cosmetics. EGF has been found in urine, saliva, milk, and plasma, but its efficient isolation remains a difficult task. With technical advances, recombinant protein purification technique has been used for EGF production. However, the recombinant EGF is still expensive and keeping it with stable activity is difficult to be used widely. Thus, a molecule that can mimic the EGF activity would be a useful alternative of EGF. Herein, we have discovered that a natural small molecule piperonylic acid shows EGF-like activity in HaCaT keratinocytes. Piperonylic acid induced EGF receptor (EGFR) activation and resulted in serial activation of the downstream modulators. The activated signaling pathway eventually up-regulated gene expression of egr-1, c-fos, c-jun, and c-myc, which are involved in cell growth and survival. Moreover, piperonylic acid showed promoting role in keratinocyte growth and survival from UVB-induced cellular damages. This study has revealed the EGF-like activity of piperonylic acid and proposed that the piperonylic acid could be a promising component for skin wound healing agents or cosmetic ingredient.

Accelerative action of topical piperonylic acid on mice full thickness wound by modulating inflammation and collagen deposition

“…We demonstrated that PA improved wound healing, providing a better-quality scar with characteristics closer to uninjured skin. Previous data in the literature [ 10 ] and the results of this study suggest that these events occur through the activation of EGFR, which is a component of the EGF family and is predominantly distributed in keratinocytes [ 9 ]. EGFR knockout mice present a serious impairment of the healing process, with delayed wound closure accompanied by a decrease in keratinocyte migration and increased edema [ 13 , 14 ].…”

“…We first carried out a dose-response experiment to determine which dose of PA to use, based on the concentration of 100 μM used in a previous study in cultured keratinocytes [ 10 ]. For this, we used 20 C57BL/6 mice randomly divided into four groups: vehicle, 10 mM PA, 1 mM PA, and 100 μM PA. Each mouse was treated daily until day 9 post-injury.…”

“…The treatment was either 20 μL of 10 μM PA (purchased from Sigma-Aldrich) or the same volume of 0.1% DMSO in Carbopol gel. This concentration was based on data from Lee et al [ 10 ].…”

“…EGF stimulates cell growth, proliferation, and survival in various tissues [ 9 ]. Lee et al [ 10 ] described that PA can activate the epidermal growth factor receptor (EGFR) and thus trigger an intracellular signaling cascade leading to the transcription of genes responsible for cell proliferation and survival, especially in cultured keratinocytes. Keratinocytes are fundamental cells in maintaining cutaneous homeostasis in the epidermal barrier and the first cells to be injured in the case of wounds [ 11 , 12 ].…”

Novel Bacterial Production of Two Different Bioactive Forms of Human Stem-Cell Factor

“…The effect of His-hSCF248 on the TF-1 cell proliferation is 400-fold stronger than that of commercial hSCF189 in terms of molar concentration. The hSCF164 induces gene expression regulation related to cell growth by activating the c-Kit receptor and downstream signaling pathway [34][35][36]. His-hSCF248 demonstrated strong activity at 1000-fold lower concentration than hSCF164 in c-Myc mRNA expression, doubling time, and cell cycle.…”