We previously reported that (-)-epigallocatechin gallate (EGCG) in green tea alters plasma membrane organization and causes internalization of epidermal growth factor receptor (EGFR), resulting in the suppression of colon cancer cell growth. In the present study, we investigated the detailed mechanism underlying EGCG-induced downregulation of EGFR in SW480 colon cancer cells. Prolonged exposure to EGCG caused EGFR degradation. However, EGCG required neither an ubiquitin ligase (c-Cbl) binding to EGFR nor a phosphorylation of EGFR at tyrosine residues, both of which are reportedly necessary for EGFR degradation induced by epidermal growth factor. In addition, EGCG induced phosphorylation of p38 mitogen-activated protein kinase (MAPK), a stress-inducible kinase believed to negatively regulate tumorigenesis, and the inhibition of p38 MAPK by SB203580, a specific p38 MAPK inhibitor, or the gene silencing using p38 MAPK-small interfering RNA (siRNA) suppressed the internalization and subsequent degradation of EGFR induced by EGCG. EGFR underwent a gel mobility shift upon treatment with EGCG and this was canceled by SB203580, indicating that EGCG causes EGFR phosphorylation via p38 MAPK. Moreover, EGCG caused phosphorylation of EGFR at Ser1046/1047, a site that is critical for its downregulation and this was also suppressed by SB203580 or siRNA of p38 MAPK. Taken together, our results strongly suggest that phosphorylation of EGFR at serine 1046/1047 via activation of p38 MAPK plays a pivotal role in EGCG-induced downregulation of EGFR in colon cancer cells.
Bioassay-guided fractionation of the methanolic extracts of the pulp and seeds of the fruits of Syzygium samarangense Merr. & Perry (Blume) led to the identification of four cytotoxic compounds and eight antioxidants on the basis of HPLC-PDA analysis, MS, and various NMR spectroscopic techniques. Three C-methylated chalcones, 2′,4′-dihydroxy-3′,5′-dimethyl-6′-methoxychalcone (1), 2′,4′-dihydroxy-3′-methyl-6′-methoxychalcone (stercurensin, 2), and 2′,4′-dihydroxy-6′-methoxychalcone (cardamonin, 3), were isolated and displayed cytotoxic activity (IC 50 = 10, 35, and 35 μM, respectively) against the SW-480 human colon cancer cell line. Also a number of known antioxidants were obtained including six quercetin glycosides: reynoutrin (4), hyperin (5), myricitrin (6), quercitrin (7), quercetin (9), and guaijaverin (10), one flavanone: (S)-pinocembrin (8), and two phenolic acids: gallic acid (11) and ellagic acid (12).
We recently found that the inhibitory effect of (-)-epigallocatechin gallate (EGCG) on epidermal growth factor (EGF) binding to the epidermal growth factor receptor (EGFR) is associated with alterations in lipid organization in the plasma membrane of colon cancer cells. Since changes in lipid organizations are thought to play a role in the trafficking of several membrane proteins, in this study we examined the effects of EGCG on cellular localization of the EGFR in SW480 cells. Treatment of the cells for 30 min with as little as 1 microg/ml of EGCG caused a decrease in cell surface-associated EGFRs and this was associated with internalization of EGFRs into endosomal vesicles. Similar effects were seen with a green fluorescent protein (GFP)-EGFR fusion protein. As expected, the EGFR protein was phosphorylated at tyrosine residues, ubiquitinated and partially degraded when the cells were treated with EGF, but treatment with EGCG caused none of these effects. The loss of EGFRs from the cell surface induced by treating the cells with EGF for 30 min persisted for at least 2 h. However, the loss of EGFRs from the cell surface induced by temporary exposure to EGCG was partially restored within 1-2 h. These studies provide the first evidence that EGCG can induce internalization of EGFRs into endosomes, which can recycle back to the cell surface. This sequestrating of inactivated EGFRs into endosomes may explain, at least in part, the ability of EGCG to inhibit activation of the EGFR and thereby exert anticancer effects.
Laryngeal elevation delay time with low-viscosity contrast medium is a recommended parameter to discriminate the corticobulbar tract and the basal ganglion lesion.
A series of 13 known compounds, including seven benzophenones [guttiferone A (1), guttiferone K (2), xanthochymol (3), guttiferone E (4), cycloxanthochymol (5), isoxanthochymol (6), and gambogenone (7)], five biflavonoids [amentoflavone (8), 3,8''-biapigenin (9), (+)-volkensiflavone (10), (+)-morelloflavone (11), and (+)-fukugiside (12)], and the xanthone derivative alloathyriol (13), were identified from the fruits of Garcinia livingstonei (Clusiaceae). This is the first time that compounds 2-7, 9, 12, and 13 have been reported in this species. The cytotoxicity of benzophenones 1 and 2 was assessed for their effect on HCT-116, HT-29, and SW-480 human colon cancer cell lines. Both compounds exhibited strong activity against HCT-116 and HT-29 cell lines with IC(50) values between 5 and 10 microM, and somewhat weaker activity with SW-480 cells (IC(50) values ranging from 18 to 25 microM).
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