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Inhibition of epidermal growth factor-induced cell transformation by tannins
Masaaki Nomura1, Hirotaka Tsukada, Daisuke Ichimatsu
1Department of Hospital Pharmacy, School of Medicine, Kanazawa University, 13-1 Takara-Machi, Kanazawa, Ishikawa 920-8641, Japan.
Abstract:
The mouse epidermal JB6 cell system is a well developed model for studying tumor promotion, and the JB6 Cl 41 promotion sensitive (P+) cell line, in which transformed colonies are induced by epidermal growth factor (EGF), was used to test the anti-tumor promoting effect of seven tannins and two triterpenoids. We found that six tannins, ellagitannins (compounds 1, 2, 3 and 4) and chromone gallates (compounds 6 and 7), significantly blocked EGF-induced cell transformation in a concentration-dependent manner. The inhibition of cell transformation by the tannins was not due to growth inhibition. The ellagitannins, but not the chromone gallates, significantly attenuated EGF-induced activator protein 1 (AP-1) activation, a transcription factor. Compounds 1 and 3, among the ellagitannins analysed, inhibited the EGF-induced phosphorylation of extracellular-signal regulated protein kinases and p38 kinases, which regulate AP-1 activation. On the other hand, compounds 3 and 4 suppressed EGF-induced phosphatidylinositol 3-kinase (PI3K) activation. In addition, all tannins that blocked cell transformation markedly inhibited EGF-induced activation of Akt, a downstream effector of PI3K. Because signal-transduction pathways, including AP-1 and PI3K pathways, have been focused as prime targets for chemopreventive phytochemicals, our results suggest that inhibition by tannins of EGF-induced neoplastic transformation in JB6 cells is related to blocking of Akt activation, and also attenuation of AP-1 activation for ellagitannins.
Insights
Certain tannins effectively inhibit tumor promotion in mouse JB6 cells by blocking key signaling pathways. These natural compounds, particularly ellagitannins, show promise as chemopreventive agents by interfering with epidermal growth factor-induced cell transformation.
Area of Science:
- * Oncology
- * Pharmacology
- * Biochemistry
Background:
- * The JB6 mouse epidermal cell system is a standard model for investigating tumor promotion.
- * Epidermal growth factor (EGF) is known to induce neoplastic transformation in JB6 Cl 41 cells.
- * Tannins and triterpenoids are natural compounds with potential anti-cancer properties.
Purpose of the Study:
- * To evaluate the anti-tumor promoting effects of seven tannins and two triterpenoids.
- * To investigate the molecular mechanisms by which these compounds inhibit EGF-induced cell transformation.
- * To identify specific signaling pathways targeted by effective tannins.
Main Methods:
- * Utilized the JB6 Cl 41 cell line to assess EGF-induced cell transformation.
- * Tested the inhibitory effects of six tannins (ellagitannins and chromone gallates) and two triterpenoids.
- * Analyzed the impact of tannins on activator protein 1 (AP-1) and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways.
- * Examined the phosphorylation of extracellular-signal regulated protein kinases and p38 kinases.
Main Results:
- * Six tannins significantly inhibited EGF-induced cell transformation in a dose-dependent manner without affecting cell growth.
- * Ellagitannins, but not chromone gallates, attenuated EGF-induced AP-1 activation.
- * Tannins inhibited EGF-induced activation of the PI3K/Akt pathway, with compounds 3 and 4 suppressing PI3K activation.
- * Compounds 1 and 3 inhibited EGF-induced phosphorylation of ERK and p38 kinases.
Conclusions:
- * Tannins, particularly ellagitannins, demonstrate significant anti-tumor promoting activity in the JB6 cell model.
- * The anti-neoplastic effects are linked to the inhibition of critical signaling pathways, including AP-1 and PI3K/Akt.
- * These findings suggest that tannins could be valuable chemopreventive agents targeting signal transduction pathways involved in cancer development.
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