As I explain in my last blog entry, green tea’s polyphenols (i.e. EGCG) are being studied intensively because of their possible cancer fighting activity in cancer cells. In laboratory experiments with animals, it has been shown that EGCG might be able to inhibit limitless replication potential, evasion of programmed death, sustained angiogenesis, and tumor cell invasiveness in cancer cells. Various studied have shown that EGCG might possibly “inhibit mitogen activation protein kinases, the activation of activator protein-1, and cell transformation” (Hou et al.).According to a study published in the Cancer Research Journal, EGCGhas been “shown to inhibit the growth of many cancer cell lines and to suppress the phosphorylation of epidermal growth factor receptor (EGFR).” As we learned a couple weeks ago in lecture, mutations that affect the Epidermal Growth Factor Receptors (EGFR) expression (amplifications and translocations) or activity (truncation) can result in the induction of cancer by being constitutively activated and phosphorylated. But so how is it that EGCG can inhibit tumor cell proliferation of cancer cells? As I mentioned in my previous blog entry, EGCG is an anti-oxidant.
An antioxidant is a molecule capable of inhibiting the oxidation of other molecules, as well as they remove free radical intermediates that cause damage to the cells by being oxidized themselves (reducing agents). In the study that I analyzed it was suggested “the inhibition of the phosphorylation of EGFR by EGCG led to the inhibition of the downstream events, such as the phosphorylation of extracellular signal-regulated kinase, signal transducers and activators of transcription 3, and Akt, resulting in the inhibition of cell growth” (Hou et al.).KYSE 150 cells treated with EGCG (20 mmol/L) for 0.5 to 24 hours showed reduction (32-85%) of phosphorylated EGFR protein at Tyr1068 site in the kinase domain. Extended treatment with EGCG induced even more reduction (80%) of EGFR protein levels, suggesting that EGCG prevented the phosphorylation in the Tyrosine-Kinase domain, which would have been previously induced by epidermal growth factors in the extracellular matrix. The inhibition of the Tyrosine-Kinase domain leads to a halt in the signaling transduction cascade that would eventually end up regulating the Ras pathway. However, very interestingly these effects were significantly affected in a negative way when superoxide dismutase (SOD), important antioxidant enzymes in cells exposed to oxygen, was added to the cells (Figure 1). To confirm that SOD has no effect on phosphorylation or protein levels, several other experiments have been done in the absence of EGCG.
Overall the study suggests that under cell conditions, EGCG is auto-oxidized and has a short half-life. It is suggested that the reaction might be catalyzed by metal ions in the culture plates, causing the formation of superoxide and EGCG radicals. The study hypothesize that superoxide, EGCG radicals, and other radicals, generated from EGCG auto-oxidation in the cell culture medium can attack and inactivate the EGFR in the outer membrane of cells, leading to the inhibition of such receptors to phosphorylate upon the addition of growth stimulating ligands.
It has been suggested that EGCG affects the auto-phosphorylation of EGFR when it directly binds to the tyrosine kinase active sites (Tyr1068) or maybe by altering the actual conformation of the proteins required for autophosphorylation to take place. Additionally, the authors suggest that this mechanism by which EGCG acts could possibly be generalized to other membrane receptor proteins because of their extracellular matrix domain, which is very vulnerable to the various radicals formed through the EGCG auto-oxidation. Intriguing questions, however, are whether EGCG can be oxidize intracellularly, or whether EGCG can be introduced into the cytosol? Moreover, it was also suggested that the H2O2 produced by EGCG auto-oxidation maybe responsible or partially responsible for the induction of EGCG-induced apoptosis, however, the levels H2O2 produced are a big factor for such mechanism.
Although this study shows a positive correlation between the inhibition of EGFR and the presence of EGCG, we have to realize that it was done in vitro, and not in humans. In humans the oxygen partial pressure is less than 40 versus 160 mm Hg that was used in the cell culture conditions. In addition, according to the study no EGCG dimers have been detected in the blood of mammals. There are many more questions that need to be investigated, such as does the auto-oxidation of EGCG occur in all tissues? Why or why not? Hopefully, in a couple years researchers will come up with a cancer treatment for humans that effectively attacks tumor cells only. For now, I will recommend you all to add drink tea to your diet not only because it might help you prevent cancer, but also because it has so many other positive effects such as prevention of food poisoning, diabetes, stroke, weight loss, lowering cholesterol, and staving of dementia.
Sources:
Hou, Zhe, Shengmin Sang, Hui You, Mao-Jung Lee, Jungil Hong, Khew-Voon Chin, and Chung S. Yang. "Mechanism of Action of (−)-Epigallocatechin-3-Gallate: Auto-oxidation–Dependent Inactivation of Epidermal Growth Factor Receptor and Direct Effects on Growth Inhibition in Human Esophageal Cancer KYSE 150 Cells ." Cancer Research . Version 65:8049-8056. American Association for Cancer Research, 1 Aug. 2005. Web. 30 May 2011. http://cancerres.aacrjournals.org/content/65/17/8049.full?sid=9c03ac6a-fff2-48b8-8b60-7245335c9d0d
