- About this Journal ·
- Abstracting and Indexing ·
- Aims and Scope ·
- Article Processing Charges ·
- Articles in Press ·
- Author Guidelines ·
- Bibliographic Information ·
- Citations to this Journal ·
- Contact Information ·
- Editorial Board ·
- Editorial Workflow ·
- Free eTOC Alerts ·
- Publication Ethics ·
- Reviewers Acknowledgment ·
- Submit a Manuscript ·
- Subscription Information ·
- Table of Contents
Journal of Oncology
Volume 2011 (2011), Article ID 540148, 7 pages
Chemoprevention of Head and Neck Cancer by Green Tea Extract: EGCG—The Role of EGFR Signaling and “Lipid Raft”
1Department of Otorhinolaryngology and Head and Neck Surgery, Kyushu Koseinenkin Hospital, 2-1-1, Kishinoura, Nishiku, Kitakyushu 806-8501, Japan
2Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka 812-8582, Japan
3Department of Gastroenterology/Internal Medicine, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan
4Deptartment of Pharmacology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan
Received 1 October 2010; Accepted 8 November 2010
Academic Editor: Pankaj Chaturvedi
Copyright © 2011 Muneyuki Masuda et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Over the past decade dose-intensified chemo-radiotherapy or molecular targeted therapy has been introduced into the treatments of head and neck squamous cell carcinoma (HNSCC) to improve the outcomes of this dismal disease. However, these strategies have revealed only limited efficacy so far. Moreover, the frequent occurrences of second primary tumor further worsen the prognosis of patients. In this context, early detection and chemoprevention appear to be a realistic and effective method to improve the prognosis as well as quality of life in patients with HNSCC. In this short paper, we discuss the potential of green tea extract, (-)-epigallocatechin-3-galate (EGCG) in HNSCC chemoprevention, focusing on two aspects that are provided recently: (1) evidence of clinical efficacy and (2) unique biological effects on “lipid raft” that emerged as an important platform of numerous biophysical functions, for example, receptor tyrosin kinases (RTKs) signalings including epidermal growth factor receptor (EGFR), which play critical roles in HNSCC carcinogenesis.
Head and neck squamous cell carcinoma (HNSCC), the sixth most common cancer worldwide, often generates from critical organs including the larynx, pharynx, oral cavity, and tongue that play indispensable roles in social, respiratory, communicative, and nutritional functions . Surgical intervention for these organs often leads to a considerable impairment of the patient’s quality of life (QOL), albeit recent remarkable progresses in reconstructive surgery. Accordingly, the intensity of conventional DNA-damaging therapies (i.e., irradiation and chemotherapy) has been strengthened to the upper limit of human tolerance of acute toxicities during the last decade . Short-term results of these treatments seem to be promising. However, it is still under debate whether these dose-intensified types of protocols would lead to the long-term overall survival as well as “functional” organ preservation, because these protocols occasionally cause considerable complications (e.g., requirement for feeding tube due to severe laryngeal and pharyngeal dysfunction) and potential treatment-related death [2–4]. Ongoing molecular targeted therapies in HNSCC revealed only marginal effects so far . In addition, the frequent occurrences of second primary tumor further worsen the prognosis of patients with HNSCC [1, 6]. As a result, the dishonorable phrase that is routinely used in the Introduction of HNSCC studies: “Despite recent advancements in treatment modalities, the overall survival and QOL of patients with HNSCC have not improved significantly over the past decade” still holds true, especially for patients with advanced stage. In view of these findings, early detection and chemoprevention appear to be realistic and effective method to improve the prognosis as well as QOL of patients with HNSCC.
2. Evidence and Perspective of EGCG in Chemoprevention
As indicated by a recent review, we have witnessed remarkable progresses in the chemoprevention research in HNSCC . A variety of natural and synthetic compounds have been shown to exert chemopreventive effects on HNSCC. Among them, a major active component of green tea extract, (-)-epigallocatechin-3-galate (EGCG), seems to be one of the most promising compounds that displays tumor suppressive effects on animal carcinogenesis model, mouse xenograft model, and a variety of cancer cell lines . Figure 1 demonstrates the chemical structure of EGCG. Despite these substantial experimental data, there has been a longstanding question about the clinical efficacy of EGCG, because in a majority of in vitro studies, EGCG exhibits biological functions at relatively higher concentrations compared to the peak plasma concentrations obtained in individuals after administrating an oral dose of EGCG or decaffeinated green tea extract (<1 μM) [8, 9]. However, recent studies provided evidence that administration of EGCG indeed has potential to reverse the process of carcinogenesis in patients with HNSCC or other human malignancies. In a phase II trial, Tsao et al. examined the effects of administration of green tea extract (GTE) capsule that contains 13.2% of EGCG for 12 weeks, three times a day at the dosage of 0 (placebo), 500, 750, or 1000 mg/m2/day on 41 patients with high-risk oral premalignant lesion. They found that two high dose arms (750 and 1000 mg/m2) revealed significantly higher response rates (58.8%) than 500 mg/m2 (36.4%) or placebo (18.2%) . The group of Shimizu, who is one of the authors of this paper, demonstrated that administration of 500 mg of GTE tablet that contain 52.5 mg of EGCG three times a day (total 1500 mg/day) for 12 months significantly inhibited the incidence of second metachronous colon adenoma in patients who underwent endoscopic polypectomy, thus 31% in control arm versus 15% in the GTE treated arm . Patients with high-grade prostate intraepithelial neoplasia received either placebo or 200 mg of GTE capsule that contain 51.8% of EGCG three times a day (total 600 mg/day) for 12 months. The GTE group displayed significantly lower incidence (3.0%) of prostate cancer compared to the placebo group (30.0%) . No serious adverse effects were observed in any of these trials. Collectively, these studies indicate that administration of 50–200 mg of EGCG three times a day for 12 months appears to be safe and clinically effective protocol. Thus, the setting appears to be ideal for validating the clinical efficacy of EGCG in a larger-scale chemoprevention study.
3. Diverse Molecular Target of EGCG
A rapidly increasing number of mechanistic studies have revealed that in addition to the antioxidant effect, EGCG inhibits tumor development and progression by modulating wide spectrum of molecular targets. Those include RTKs: epidermal growth factor receptor (EGFR), erbB2/Her2, erbB3/Her3, erbB4/Her4, vascular endothelial growth factor receptor (VEGFR), platelet derived growth factor receptor (PDGR), insulin-like growth factor receptor (IRGFR) and hepatocellular growth factor receptor (HGFR), mitogen activated protein kinase (MAPK), proteasomes, matrix metro proteases (MMPs), cyclin-dependent kinases (CDKs), p53, DNA methyltransferase, Bcl-2, VEGF, reactive oxygen species (ROS,) 67 kDa laminin receptor (67LR), vimentin, phosphatidylinositol-3-kinase (PI3K)-Akt, NF-κB, signal transducers and activators of transcription 3 (Stat3), and AP-1. These surprisingly diverse interactions between EGCG and target molecules or pathways are summarized in a recent comprehensive review . In this short paper, we will mainly discuss the effects of EGCG on receptor tyrosin kinases (RTKs), especially EGFR, and their cell surface vessel, “lipid rafts,” that have emerged as a critical target of EGCG as well as an essential platform for signal transduction.
4. The Role and Mechanism of EGFR Activation in HNSCC Carcinogenesis
In 1990s, Grandis et al. demonstrated that EGFR and its ligand transforming growth factor-α (TGF-α) mRNA were overexpressed in approximately 90% of HNSCC tumors, and overexpression of these two proteins was significantly associated with poor prognosis of patients with HNSCC [13, 14]. To date, numerous studies have revealed that EGFR signaling orchestrates tumor development and progression by activating several downstream signal transduction pathways including MAPK, Stat3, PI3K-Akt-mTOR, protein kinase C (PKC), and NF-κB [15–17]. Several mechanisms have been postulated to explain aberrant EGFR signaling in human malignancies [15, 16]. Those include (1) receptor overexpression, (2) autocrine or paracrine activation by ligand overexpression or excessive ligand cleavage from cell surface by ADAM family metalloprotease, (3) gene amplification, (4) ligand independent activation through other receptor systems (e.g., erbB2), (5) constitutive active EGFR mutants: somatic activating mutation or truncated EGFRvIII, and/or (6) loss of negative regulation (e.g., EGFR degradation). Despite EGFR is one of the most extensively investigated molecules in HNSCC pathogenesis, the predominant mechanism of EGFR activation remains elusive. The EGFR gene amplification was observed only in 7 out of 33 patients with HNSCC, and intriguingly this amplification did not lead to protein overexpression . However a recent study demonstrated that 49 out of 145 oral premalignant lesions displayed EGFR protein overexpression which was associated with relatively high incidence (41%) of EGFR gene copy . Thus, the correlation between the EGFR gene amplification and protein expression is still under debate. The possibility of excessive cleavage of TGF-α and amphiregulin was demonstrated in HNSCC cell lines  but is not confirmed in clinical samples. The reported rates of somatic mutation of EGFR in HNSCC range as low as 7-8% [21–23]. Sok et al. found EGFRvIII expression in 42% of 33 HNSCC samples employing both immunohistochemical and RT-PCR assays . In contrast, Yang et al. reported only 15% of EGFRvIII positive rates in 39 Chinese laryngeal cancer . Interestingly, in 82 HNSCC samples from Japanese population, EGFR vIII was not detected . Here again, the role of EGFRvIII in HNSCC is still controversial. The mechanism of EGFR internalization, degradation and recycling is a quite essential aspect that is closely associated with EGFR signaling . However, there were few reports, which investigated this mechanism in HNSCC. We recently examined the role of multiadaptor protein c-Cbl interacting protein of 85 kDa (CIN85)  in HNSCC focusing on its role in EGFR signaling pathway . In this study, we found that (1) CIN85 significantly facilitates EGFR internalization without apparently altering the levels of phosphorylated EGFR protein (i.e., EGFR signal intensity), consistent with the theory that TGF-α bound EGFRs are mainly sorted to the recycling-back pathway escaping from degradation, while a majority of EGF-bound EGFRs are processed via the degradation pathway , (2) TGF-α bound EGFR receptor signals in the cytosol as well as on plasma membrane, activating ras-MAPK cascade (ras-enriched small cytosolic nanoparticles, “rasosomes,” might contribute to this signaling ), (3) CIN85 silencing, therefore, inhibits EGFR internalization and activation of ras-MAPK cascade, and (4) CIB85 overexpression observed in 40% of HNSCC tumor samples contributes to the development of EGFR/ras-MAPK activation loop (Figures 2 and 3(a)). This model, at least in part, accounts for the reason why not EGFR but TGF-α is prominent mitogen in HNSCC development and progression. Nevertheless, it should be emphasized that the mechanism that causes TGF-α and EGFR overexpression in HNSCC remains elusive, although almost 20 years have passed since Grandis et al. [13, 14] first reported the significance of this overexpression.
5. EGCG Inhibits EGFR: The Role of Lipid Raft
Irrespective of the mechanisms which underlie EGFR activation in HNSCC, it was discovered by Liang et al. that EGCG can directly inhibit the binding of EGF to EGFR and thereby inhibits EGFR signaling . Consistent with this finding, we first provided evidence that EGCG indeed inhibits EGFR activation in HNSCC cell line that displays autocrine activation of EGFR by TGF-α . We further examined the effect of EGCG on erbB2/Her2 employing HNSCC and breast cancer cell lines, and found that EGCG can inhibit the erbB2/Her2 activation, demonstrating the first example of erbB2/Her2 inhibition by EGCG in human malignancies . Thereafter, we and other investigators confirmed the inhibitory effects of EGCG on other RTKs including erbB3/Her3, erbB4/Her4, IGFR, PDGFR, FGFR, and VEGFR employing a variety of cancer cell lines derived from different organs [33–38]. These ubiquitous inhibitory effects of EGCG on a series of RTKs, combined with the fact that the inhibitory effect of EGCG on EGF/EGFR binding was found only in a subcellular system , raised a question that EGCG might inhibit RTKs by a more general mechanism.
Due to recent remarkable progresses in methods to analyze the structure, dynamic assembly, and function of nanoscale molecules, it is beginning apparent that cell membranes play critical roles in coordinating a variety of biochemical reactions including RTKs signal transduction [39–42]. Nanoscale transient membrane domains, “lipid rafts,” that are enriched with cholesterol, glycosphingolipids, glycosylphosphatidylinositol-anchored protein, caveolin-1, and signaling molecules, function as signaling platforms [39–41]. Among the RTKs, the interaction of EGFR with lipid rafts is most well understood . Activation of EGFR by ligand and consequent signal transduction begins at lipid rafts, while its internalization occurs at clathrin-coated pit by further recruiting the E3 ubiquitin ligase Cbl, CIN85, and endorphins. The role of CIN85 in EGFR signal transduction in HNSCC was discussed in the previous section. These observations made us to hypothesize that EGCG might inhibit the activation of EGFR or other RTKs by altering the formation of lipid rafts.
So far through a series of three studies [43–45] we found that (1) EGCG alters lipid organization on the plasma membrane, (2) EGCG promote the internalization of nonactivated monomer EGFR into cytosol, thus, inhibiting the activation of EGFR by EGF, (3) as a result, treatment with EGCG causes marked reduction of phosphorylated (activated) EGFRs, that are otherwise preferentially present in lipid rafts, (4) EGCG-induced EGFR internalization requires neither the binding of c-Cbl to EGFR nor a phosphorylation of EGFR at tyrosine residue, suggesting that this internalization is mediated by a different mechanism that is observed in EGF-treated cells, and (5) phosphorylation of EGFR at serine1046/1047 mediated by p38MAPK is essential for EGCG-induced EGFR internalization (Figure 3(b)).
In parallel with our findings, a Japanese research group discovered that 67LR, a constituent protein of lipid rafts, is an important binding target of EGCG . 67LR is a nonintegrin laminin receptor, which is overexpressed on cell surface of various types of tumors, and the expression level of this protein strongly correlates with the aggressive phenotypes of tumor, albeit its role in HNSCC carcinogenesis is not investigated so far [47, 48]. Intriguingly, the predicted value for the binding of EGFG to 67LR is as low as 40 nM, and physiological concentration of EGCG indeed inhibits the growth of human lung cancer cell line in a 67LR-dependent manner . Although it is not clear whether the above-mentioned inhibition of EGFR by EGCG is relevant to 67LR, this finding also provides evidence that EGCG exerts antitumor effects through the interaction with lipid rafts protein.
As mentioned in the “Introduction,” the EGFR targeted therapies, either used alone or in combination with radiation, have shown only limited efficacy so far, albeit its significant role in HNSCC carcinogenesis . One of possible explanations for this insensitivity is that other growth factors or cytokines can surrogate EGFR signaling and activate downstream signal cascades including MAPK, Stat3, and PI3k-Akt. Then, HNSCC can relatively easily escape from EGFR dependency. However, Zhang et al. demonstrated that EGCG can synergistically enhance the growth inhibitory effects of EGFR tyrosine kinase inhibitor, erlotinib, both in vitro and in animal xenograft models employing HNSCC cell lines . Consistent with our findings, treatment of EGCG significantly enhanced EGFR internalization that was not observed with treatment of erlotinib alone. Thus, they speculate that this internalization and consequent degradation of EGFR might be a major mechanism that accounts for this synergistic interaction. However, given the fact that a majority of growth factors or cytokines, which can surrogate EGFR signaling, utilize lipid rafts as signaling platforms , this synergistic interaction might be caused through the general inhibitory effects of EGCG on these growth factors or cytokines in lipid rafts. Thus, the addition of EGCG to RTKs targeting therapies might be an attractive strategy, which leads to the prevention of drug-tolerance, as is frequently observed in several clinical settings.
Considering the tantalizingly marginal improvement in the treatment outcomes of patients with HNSCC, it is urgent and critical to develop novel strategy based on early detection and chemoprevention. Among numerous putative chemopreventive agents, EGCG appears to be one of the most promising natural compounds based on accumulated data and, in particular, two novel findings provided recently: (1) clinical efficacy and (2) unique biological effects on lipid rafts that are an important platform of numerous biophysical functions including RTKs signalings. A larger-scale clinical study of EGCG is highly recommended.
This paper is dedicated to the authors’ mentor Professor I. B. Weinstein with loving memories. This study was supported in part by fund from Grants-in-Aid for Scientific Research (C): 21592195 to M. Masuda
Conflict of Interests
The authors disclose no conflict of interests.
- K. D. Hunter, E. K. Parkinson, and P. R. Harrison, “Profiling early head and neck cancer,” Nature Reviews Cancer, vol. 5, no. 2, pp. 127–135, 2005.
- J. Corry, L. J. Peters, and D. Rischin, “Optimising the therapeutic ratio in head and neck cancer,” The Lancet Oncology, vol. 11, no. 3, pp. 287–291, 2010.
- D. I. Rosenthal, J. S. Lewin, and A. Eisbruch, “Prevention and treatment of dysphagia and aspiration after chemoradiation for head and neck cancer,” Journal of Clinical Oncology, vol. 24, no. 17, pp. 2636–2643, 2006.
- M. Machtay, J. Moughan, A. Trotti et al., “Factors associated with severe late toxicity after concurrent chemoradiation for locally advanced head and neck cancer: an RTOG analysis,” Journal of Clinical Oncology, vol. 26, no. 21, pp. 3582–3589, 2008.
- J. Bernier, S. M. Bentzen, and J. B. Vermorken, “Molecular therapy in head and neck oncology,” Nature Reviews Clinical Oncology, vol. 6, no. 5, pp. 266–277, 2009.
- J. W. Kim, A. R.M.R. Amin, and D. M. Shin, “Chemoprevention of head and neck cancer with green tea polyphenols,” Cancer Prevention Research, vol. 3, no. 8, pp. 900–909, 2010.
- C. S. Yang, X. Wang, G. Lu, and S. C. Picinich, “Cancer prevention by tea: animal studies, molecular mechanisms and human relevance,” Nature Reviews Cancer, vol. 9, no. 6, pp. 429–439, 2009.
- C. S. Yang, L. Chen, M. J. Lee, D. Balentine, M. C. Kuo, and S. P. Schantz, “Blood and urine levels of tea catechins after ingestion of different amounts of green tea by human volunteers,” Cancer Epidemiology Biomarkers and Prevention, vol. 7, no. 4, pp. 351–354, 1998.
- H. H. S. Chow, Y. Cai, D. S. Alberts et al., “Phase I pharmacokinetic study of tea polyphenols following single-dose administration of epigallocatechin gallate and Polyphenon E,” Cancer Epidemiology Biomarkers and Prevention, vol. 10, no. 1, pp. 53–58, 2001.
- A. S. Tsao, D. Liu, J. Martin et al., “Phase II randomized, placebo-controlled trial of green tea extract in patients with high-risk oral premalignant lesions,” Cancer Prevention Research, vol. 2, no. 11, pp. 931–941, 2009.
- M. Shimizu, Y. Fukutomi, M. Ninomiya et al., “Green tea extracts for the prevention of metachronous colorectal adenomas: a pilot study,” Cancer Epidemiology Biomarkers and Prevention, vol. 17, no. 11, pp. 3020–3025, 2008.
- S. Bettuzzi, M. Brausi, F. Rizzi, G. Castagnetti, G. Peracchia, and A. Corti, “Chemoprevention of human prostate cancer by oral administration of green tea catechins in volunteers with high-grade prostate intraepithelial neoplasia: a preliminary report from a one-year proof-of-principle study,” Cancer Research, vol. 66, no. 2, pp. 1234–1240, 2006.
- J. R. Grandis, M. F. Melhem, E. L. Barnes, and D. J. Tweardy, “Quantitative immunohistochemical analysis of transforming growth factor- α and epidermal growth factor receptor in patients with squamous cell carcinoma of the head and neck,” Cancer, vol. 78, no. 6, pp. 1284–1292, 1996.
- J. R. Grandis, M. F. Melhem, W. E. Gooding et al., “Levels of TGF-α and EGFR protein in head and neck squamous cell carcinoma and patient survival,” Journal of the National Cancer Institute, vol. 90, no. 11, pp. 824–832, 1998.
- S. Kalyankrishna and J. R. Grandis, “Epidermal growth factor receptor biology in head and neck cancer,” Journal of Clinical Oncology, vol. 24, no. 17, pp. 2666–2672, 2006.
- C. W. M. Reuter, M. A. Morgan, and A. Eckardt, “Targeting EGF-receptor-signalling in squamous cell carcinomas of the head and neck,” British Journal of Cancer, vol. 96, no. 3, pp. 408–416, 2007.
- M. Masuda, T. Wakasaki, M. Suzui, S. Toh, A. K. Joe, and I. B. Weinstein, “Stat3 orchestrates tumor development and progression: the Achilles' heel of head and neck cancers?” Current Cancer Drug Targets, vol. 10, no. 1, pp. 117–126, 2010.
- M. Mrhalova, J. Plzak, J. Betka, and R. Kodet, “Epidermal growth factor receptor—its expression and copy numbers of EGFR gene in patients with head and neck squamous cell carcinomas,” Neoplasma, vol. 52, no. 4, pp. 338–343, 2005.
- M. T. Benchekroun, P. Saintigny, S. M. Thomas et al., “Epidermal growth factor receptor expression and gene copy number in the risk of oral cancer,” Cancer Prevention Research, vol. 3, no. 7, pp. 800–809, 2010.
- Q. Zhang, S. M. Thomas, S. Xi et al., “Src family kinases mediate epidermal growth factor receptor ligand cleavage, proliferation, and invasion of head and neck cancer cells,” Cancer Research, vol. 64, no. 17, pp. 6166–6173, 2004.
- C. Willmore-Payne, J. A. Holden, and L. J. Layfield, “Detection of EGFR- and HER2-activating mutations in squamous cell carcinoma involving the head and neck,” Modern Pathology, vol. 19, no. 5, pp. 634–640, 2006.
- W. L. Jong, H. S. Young, Y. K. Su et al., “Somatic mutations of EGFR gene in squamous cell carcinoma of the head and neck,” Clinical Cancer Research, vol. 11, no. 8, pp. 2879–2882, 2005.
- T. Hama, Y. Yuza, Y. Saito et al., “Prognostic significance of epidermal growth factor receptor phosphorylation and mutation in head and neck squamous cell carcinoma,” Oncologist, vol. 14, no. 9, pp. 900–908, 2009.
- J. C. Sok, F. M. Coppelli, S. M. Thomas et al., “Mutant epidermal growth factor receptor (EGFRvIII) contributes to head and neck cancer growth and resistance to EGFR targeting,” Clinical Cancer Research, vol. 12, no. 17, pp. 5064–5073, 2006.
- B. Yang, J. Chen, X. Zhang, and J. Cao, “Expression of Epidermal Growth Factor Receptor variant III in laryngeal carcinoma tissues,” Auris Nasus Larynx, vol. 36, no. 6, pp. 682–687, 2009.
- A. Sorkin and L. K. Goh, “Endocytosis and intracellular trafficking of ErbBs,” Experimental cell research, vol. 315, no. 4, pp. 683–696, 2009.
- I. Dikic, “CIN85/CMS family of adaptor molecules,” FEBS Letters, vol. 529, no. 1, pp. 110–115, 2002.
- T. Wakasaki, M. Masuda, H. Niiro et al., “A critical role of c-Cbl-interacting protein of 85 kDa in the development and progression of head and neck squamous cell carcinomas through the Ras-ERK pathway,” Neoplasia, vol. 12, no. 10, pp. 789–796, 2010.
- B. Rotblat, O. Yizhar, R. Haklai, U. Ashery, and Y. Kloog, “Ras and its signals diffuse through the cell on randomly moving nanoparticles,” Cancer Research, vol. 66, no. 4, pp. 1974–1981, 2006.
- Y. U. C. Liang, S. Y. Lin-shiau, C. F. Chen, and J. K. Lin, “Suppression of extracellular signals and cell proliferation through EGF receptor binding by (-)-epigallocatechin gallate in human A431 epidermoid carcinoma cells,” Journal of Cellular Biochemistry, vol. 67, no. 1, pp. 55–65, 1997.
- M. Masuda, M. Suzui, and I. B. Weinstein, “Effects of epigallocatechin-3-gallate on growth, epidermal growth factor receptor signaling pathways, gene expression, and chemosensitivity in human head and neck squamous cell carcinoma cell lines,” Clinical Cancer Research, vol. 7, no. 12, pp. 4220–4229, 2001.
- M. Masuda, M. Suzui, J. T. E. Lim, and I. B. Weinstein, “Epigallocatechin-3-gallate inhibits activation of HER-2/neu and downstream signaling pathways in human head and neck and breast carcinoma cells,” Clinical Cancer Research, vol. 9, no. 9, pp. 3486–3491, 2003.
- M. Masuda, M. Suzui, J. T. E. Lim, A. Deguchi, J. W. Soh, and I. B. Weinstein, “Epigallocatechin-3-gallate decreases VEGF production in head and neck and breast carcinoma cells by inhibiting EGFR-related pathways of signal transduction,” Journal of Experimental Therapeutics and Oncology, vol. 2, no. 6, pp. 350–359, 2002.
- M. Shimizu, A. Deguchi, Y. Hara, H. Moriwaki, and I. B. Weinstein, “EGCG inhibits activation of the insulin-like growth factor-1 receptor in human colon cancer cells,” Biochemical and Biophysical Research Communications, vol. 334, no. 3, pp. 947–953, 2005.
- M. Shimizu, A. Deguchi, A. K. Joe, J. F. Mckoy, H. Moriwaki, and I. B. Weinstein, “EGCG inhibits activation of HER3 and expression of cyclooxygenase-2 in human colon cancer cells,” Journal of Experimental Therapeutics and Oncology, vol. 5, no. 1, pp. 69–78, 2005.
- M. Shimizu, A. Deguchi, J. T. E. Lim, H. Moriwaki, L. Kopelovich, and I. B. Weinstein, “(-)-Epigallocatechin gallate and polyphenon E inhibit growth and activation of the epidermal growth factor receptor and human epidermal growth factor receptor-2 signaling pathways in human colon cancer cells,” Clinical Cancer Research, vol. 11, no. 7, pp. 2735–2746, 2005.
- M. Shimizu, Y. Shirakami, and H. Moriwaki, “Targeting receptor tyrosine kinases for chemoprevention by green tea catechin, EGCG,” International Journal of Molecular Sciences, vol. 9, no. 6, pp. 1034–1049, 2008.
- M. Shimizu, Y. Shirakami, H. Sakai et al., “(-)-Epigallocatechin gallate inhibits growth and activation of the VEGF/VEGFR axis in human colorectal cancer cells,” Chemico-Biological Interactions, vol. 185, no. 3, pp. 247–252, 2010.
- C. Le Roy and J. L. Wrana, “Clathrin- and non-clathrin-mediated endocytic regulation of cell signalling,” Nature Reviews Molecular Cell Biology, vol. 6, no. 2, pp. 112–126, 2005.
- S. K. Patra, “Dissecting lipid raft facilitated cell signaling pathways in cancer,” Biochimica et Biophysica Acta, vol. 1785, no. 2, pp. 182–206, 2008.
- P. Lajoie, J. G. Goetz, J. W. Dennis, and I. R. Nabi, “Lattices, rafts, and scaffolds: domain regulation of receptor signaling at the plasma membrane,” Journal of Cell Biology, vol. 185, no. 3, pp. 381–385, 2009.
- D. Lingwood and K. Simons, “Lipid rafts as a membrane-organizing principle,” Science, vol. 327, no. 5961, pp. 46–50, 2010.
- S. Adachi, T. Nagao, H. I. Ingolfsson et al., “The inhibitory effect of (-)-epigallocatechin gallate on activation of the epidermal growth factor receptor is associated with altered lipid order in HT29 colon cancer cells,” Cancer Research, vol. 67, no. 13, pp. 6493–6501, 2007.
- S. Adachi, T. Nagao, S. To et al., “(-)-Epigallocatechin gallate causes internalization of the epidermal growth factor receptor in human colon cancer cells,” Carcinogenesis, vol. 29, no. 10, pp. 1986–1993, 2008.
- S. Adachi, M. Shimizu, Y. Shirakami et al., “(-)-Epigallocatechin gallate downregulates EGF receptor via phosphorylation at Ser1046/1047 by p38 MAPK in colon cancer cells,” Carcinogenesis, vol. 30, no. 9, pp. 1544–1552, 2009.
- H. Tachibana, K. Koga, Y. Fujimura, and K. Yamada, “A receptor for green tea polyphenol EGCG,” Nature Structural and Molecular Biology, vol. 11, no. 4, pp. 380–381, 2004.
- D. Umeda, S. Yano, K. Yamada, and H. Tachibana, “Green tea polyphenol epigallocatechin-3-gallate signaling pathway through 67-kDa laminin receptor,” Journal of Biological Chemistry, vol. 283, no. 6, pp. 3050–3058, 2008.
- S. K. Patra, F. Rizzi, A. Silva, D. O. Rugina, and S. Bettuzzi, “Molecular targets of (-)-epigallocatechin-3-gallate (EGCG): specificity and interaction with membrane lipid rafts,” Journal of Physiology and Pharmacology, vol. 59, supplement 9, pp. 217–235, 2008.
- X. Zhang, H. Zhang, M. Tighiouart et al., “Synergistic inhibition of head and neck tumor growth by green tea (-)-epigallocatechin-3-gallate and EGFR tyrosine kinase inhibitor,” International Journal of Cancer, vol. 123, no. 5, pp. 1005–1014, 2008.