Targeting of the preventive effect of EGCG ((-)-epigallocatechin-3-gallate) on lipid rafts in colon cancer cells

• Project/Area Number: 20790490
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Gastroenterology
• Research Institution: Gifu University
• Principal Investigator: SEIJI Adachi Gifu University, 大学院・医学系研究科, 助教 (50467205)
• Project Period (FY): 2008 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2009: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2008: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: EGCG / EGFR / p38MAPキナーゼ / 脂質ラフト / 内在化 / 受容体チロシンキナーセ / p38MAPK / セリンリン酸化 / 受容体チロシンキナーゼ / p38 MAPK / internalization / recycle

Research Abstract

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, concurrently inducing phosphorylation of p38 mitogen-activated protein kinase (MAPK). The inhibition of p38 MAPK by SB203580, a specific p38 MAPK inhibitor, or p38 MAPK-siRNA suppressed the internalization and subsequent degradation of EGFR induced by EGCG. Moreover, EGCG caused phosphorylation of EGFR at Ser1046/1047, a site which 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.

Research Products

• [Journal Article] HSP90 inhibitors induce down-regulation of EGF receptor via p38 MAPK-mediated phosphorylation at Ser1046/1047 in human pancreatic cancer cells. (2010)
  • Author(s): Adachi S, Yasuda I, Nakashima M, Yamauchi T, Yamauchi J, Natsume H, Moriwaki H, Kozawa O
  • Journal Title: Oncol Rep 23 Pages: 1709-14
  • Peer Reviewed
• [Journal Article] Rho-kinase regulates negatively the epidermal growth factor-stimulated colon cancer cell proliferation. (2010)
  • Author(s): Nakashima M, Adachi S, Yasuda I, Yamauchi T, Kozawa O, Moriwaki H
  • Journal Title: Int J Oncol 36 Pages: 585-92
  • Peer Reviewed
• [Journal Article] Rho-kinase limits FGF-2-stimulated VEGF release in osteoblasts. (2010)
  • Author(s): Natsume H, Tokuda H, Adachi S, Takai S, Matsushima-Nishiwaki R, Kato K, Minamitani C, Niida S, Mizutani J, Kozawa O, Otsuka T
  • Journal Title: Bone 46 Pages: 1068-1074
  • Peer Reviewed
• [Journal Article] Inhibition by minodronate of basic fibroblast growth factor-stimulated vascular endothelial growth factor synthesis in osteoblast-like cells. (2010)
  • Author(s): Tokuda H, Adachi S, Matsushima-Nishiwaki R, Hanai Y, Takai S, Harada A, Kozawa O
  • Journal Title: Mol Med Rep 3 Pages: 167-171
  • Peer Reviewed
• [Journal Article] p70 S6 kinase limits tumor necrosis factor-alpha-induced interleukin-6 synthesis in osteoblast-like cells. (2010)
  • Author(s): Minamitani C, Tokuda H, Adachi S, Matsushima-Nishiwaki R, Yamauchi J, Kato K, Natsume H, Mizutani J, Kozawa O, Otsuka T
  • Journal Title: Mol Cell Endocrinol 315 Pages: 195-200
  • Peer Reviewed
• [Journal Article] The involvement of thromboxane A2 in the elevation of soluble CD40 ligand levels in atherosclerotic patients (2010)
  • Author(s): Enomoto Y, Adachi S, Matsushima-Nishiwaki R, Doi T, Niwa M, Akamatsu S, Tokuda H, Yoshimura S, Ogura S, Iwama T, Kozawa O
  • Journal Title: Atherosclerosis 209 Pages: 414-421
  • Peer Reviewed
• [Journal Article] (-)-Epigallocatechin gallate prevents carbon tetrachloride-induced rat hepatic fibrosis by inhibiting the expression of the PDGFRbeta and IGF-1R. (2010)
  • Author(s): Yasuda Y, Shimizu M, Sakai H, Iwasa J, Kubota M, Adachi S, Osawa Y, Tsurumi H, Hara Y, Moriwaki H
  • Journal Title: Chem Biol Interact 182 Pages: 159-164
  • Peer Reviewed
• [Journal Article] Roloxifene enhances spontaneous microaggregation of platelets through up-regulation of p44/p42 MAP kinase: a case report. (2010)
  • Author(s): Tokuda H, Harada A, Adachi S, Matsushima-Nishiwaki R, Natsume H, Minamitani C, Mizutani J, Otsuka T, Kozawa O
  • Journal Title: Osteoporosis Int 21 Pages: 189-93
  • Peer Reviewed
• [Journal Article] HSP90 inhibitors induce down-regulation of EGF receptor via p38 MAP K-mediated phosphorylation at Ser1046/1047 in human pancreatic cancer cells (2010)
  • Author(s): Adachi S, et al.
  • Journal Title: Oncology Reports (in press)
  • Peer Reviewed
• [Journal Article] Antithrombin III suppresses ADP-induced platelet granule secretion: Inhibition of HSP27 phosphorylation. (2009)
  • Author(s): Doi T, Adachi S, Takai S, Matsushima-Nishiwaki R, Kato H, Enomoto Y, Minamitani C, Otsuka T, Tokuda H, Akamatsu S, Iwama T, Kozawa O, Ogura S
  • Journal Title: Arch Biochem Biophys 489 Pages: 62-7
  • Peer Reviewed
• [Journal Article] (-)-Epigallocatechin gallate downregulates EGF receptor via its phosphorylation at Ser1046/1047 mediated by p38 MAP kinase in colon cancer cells. (2009)
  • Author(s): Adachi S, Shimizu M, Shirakami Y, Yamauchi J, Natsume H, Matsushima-Nishiwaki R, To S, Weinstein IB, Moriwaki H, Kozawa O
  • Journal Title: Carcinogenesis 30 Pages: 1544-52
  • Peer Reviewed
• [Journal Article] αB-crystallin suppresses ADP-induced granule secretion from human platelets. (2009)
  • Author(s): Enomoto Y, Adachi S, Matsushima-Nishiwaki R, Niwa M, Tokuda H, Akamatsu S, Doi T, Kato H, Yoshimura S, Ogura S, Iwama T, Kozawa O
  • Journal Title: FEBS Lett 583 Pages: 2464-8
  • Peer Reviewed
• [Journal Article] Involvement of Rho-kinase in TGF-b-stimulated heat shock protein 27 induction in osteoblasts. (2009)
  • Author(s): Natsume H, Mizutani J, Adachi S, Matsushima-Nishiwaki R, Manamitani C, Tokuda H, Kozawa O, Otsuka T
  • Journal Title: Mol Med Rep 3 Pages: 167-171
  • Peer Reviewed
• [Journal Article] Level of p38 MAP kinase activation is a biomarker of platelet hyper-aggregation induced by collagen in patients with DM. (2009)
  • Author(s): Hanai Y, Adachi S, Yasuda I, Takai S, Matsushima-Nishiwaki R, Kato H, Akamatsu S, Ogura S, Kozawa O, Tokuda H
  • Journal Title: Life Sci 26 Pages: 386-94
  • Peer Reviewed
• [Journal Article] (-)-Epigallocatechin gallate suppresses the growth of human hepatocellular carcinoma cells by inhibiting activation of the VEGF/VEGFR axis. (2009)
  • Author(s): Shirakami Y, Shimizu M, Adachi S, Sakai H, Nakagawa T, Yasuda Y, Tsurumi H, Hara Y, Moriwaki H
  • Journal Title: Cancer Sci 100 Pages: 1957-62
  • Peer Reviewed
• [Journal Article] Involvement of Rho-kinase in prostaglandin E1-stimulated VEGF synthesis through stress-activated protein kinase/c-Jun N-terminal kinase in osteoblast-like MC3T3-E1 cells. (2009)
  • Author(s): Adachi S, Tokuda H, Matsushima-Nishiwaki R, Natsume H, Minamitani C, Mizutani J, Otsuka T, Kozawa O
  • Journal Title: Pro & Other Lipid Med 90 Pages: 1-6
  • Peer Reviewed
• [Journal Article] (-)-Epigallocatechin gallate attenuates the induction of HSP27 stimulated by sphingosine 1-phosphate via suppression of phosphatidylinositol 3-kinase/Akt pathway in osteoblasts. (2009)
  • Author(s): Natsume H, Adachi S, Takai S, Tokuda H, Matsushima-Nishiwaki R, Yamauchi J, Kato H, Kato K, Mizutani J, Otsuka T, Kozawa O
  • Journal Title: Int J Mol Med 24 Pages: 197-203
  • Peer Reviewed
• [Journal Article] Involvement of Rho-kinase in tumor necrosis factor-a-induced interleukin-6 release from C6 glioma cells. (2009)
  • Author(s): Yamaguchi S, Tanabe K, Takai S, Matsushima-Nishiwaki R, Adachi S, Iida H, Kozawa O, Dohi S
  • Journal Title: Neurochem Int 55 Pages: 438-45
  • Peer Reviewed
• [Journal Article] 緑茶カテキンの大腸癌細胞増殖抑制の新規メカニズム～脂質ラフトでのEGFR pathwayの阻害～ (2009)
  • Author(s): 足立政治, I. Bernard Weinstein, 森脇久隆
  • Journal Title: 消化器病学の進歩-原点から未来への情報発信-東京:医学書院 Pages: 404-408
• [Journal Article] Involvement of Rho-kinase in sphingosine 1-phosphate-stimulated HSP27 induction in osteoblasts. (2009)
  • Author(s): Minamitani C, Otsuka T, Takai S, Matsushima-Nishiwaki R, Adachi S, Hanai Y, Mizutani J, Tokuda H, Kozawa O
  • Journal Title: Int J Mol Med 24 Pages: 77-82
  • Peer Reviewed
• [Journal Article] p38 MAP kinase controls EGF receptor downregulation via phosphorylation at Ser1046/1047. (2009)
  • Author(s): Adachi S, Natsume H, Yamauchi J, Matsushima-Nishiwaki R, Joe AK, Moriwaki H, Kozawa O
  • Journal Title: Cancer Lett 277 Pages: 108-13
  • Peer Reviewed
• [Journal Article] Tacrolimus but not cyclosporine A enhances FGF-2-induced VEGF release in osteoblasts. (2009)
  • Author(s): Yamauchi J, Takai S, Matsushima-Nishiwaki R, Adachi S, Minamitani C, Natsume H, Mizutani J, Otsuka T, Takeda J, Harada A, Kozawa O, Tokuda H
  • Journal Title: Int J Mol Med 23 Pages: 267-72
  • Peer Reviewed
• [Journal Article] Rho-kinase inhibitors decrease TGF-<beta>-stimulated VEGF synthesis through stress-activated protein kinase/c-Jun N-terminal kinase in osteoblasts. (2009)
  • Author(s): Kuno M, Takai S, Matsushima-Nishiwaki R, Minamitani C, Mizutani J, Otsuka T, Harada A, Adachi S, Kozawa O, Tokuda H
  • Journal Title: Biochem Pharmacol 77 Pages: 196-203
  • Peer Reviewed
• [Journal Article] p38 MAP kinase controls EGF receptor downregulation via phosphorylation at Ser1046/1047 (2009)
  • Author(s): Adachi S, et al.
  • Journal Title: Cancer Letters 277 Pages: 108-113
  • Peer Reviewed
• [Journal Article] (-)-Epigallocatechin gallate downregulates EGF receptor via its phosphory lation at Ser1046/1047 mediated by p38 MAP kinase in colon cancer cells (2009)
  • Author(s): Adachi S, et al.
  • Journal Title: Carcinogenesis 30 Pages: 1544-1552
  • Peer Reviewed
• [Journal Article] p38 MAP kinase controls EGF receptor downregulation via phosphorylation at Ser1046/1047 (2009)
  • Author(s): Adachi S, et.al.
  • Journal Title: Cancer Letters 277 Pages: 108-113
  • Peer Reviewed
• [Journal Article] (-)-Epigallocatechin gallate reduces platelet-derived growth factor-BB-stimulated interleukin-6 synthesis in osteoblasts: suppression of SAPK/JNK. (2008)
  • Author(s): Takai S, Matsushima-Nishiwaki R, Adachi S, Natsume H, Minamitani C, Mizutani J, Otsuka T, Tokuda H, Kozawa O
  • Journal Title: Mediators Inflamm Pages: 291808-291808
  • Peer Reviewed
• [Journal Article] Function of Rho-kinase in prostaglandin D(2)-induced interleukin-6 synthesis in osteoblasts. (2008)
  • Author(s): Tokuda H, Takai S, Matsushima-Nishiwaki R, Hanai Y, Adachi S, Minamitani C, Mizutani J, Otsuka T, Kozawa O
  • Journal Title: Prostaglandins Leukot Essent Fatty Acids 79 Pages: 41-6
  • Peer Reviewed
• [Journal Article] Involvement of Rho-kinase in prostaglandin F(2alpha)-stimulated interleukin-6 synthesis via p38 mitogen-activated protein kinase in osteoblasts. (2008)
  • Author(s): Minamitani C, Otsuka T, Takai S, Matsushima-Nishiwaki R, Adachi S, Hanai Y, Mizutani J, Tokuda H, Kozawa O
  • Journal Title: Mol Cell Endocrinol 291 Pages: 27-32
  • Peer Reviewed
• [Journal Article] Phosphorylated heat shock protein 27 represses growth of hepatocellular carcinoma via inhibition of extracellular-signal-regulated kinase. (2008)
  • Author(s): Matsushima-Nishiwaki R, Takai S, Adachi S, Minamitani C, Yasuda E, Noda T, Kato K, Toyoda H, Kaneoka Y, Yamaguchi A, Kumada T, Kozawa O
  • Journal Title: J Biol Chem 283 Pages: 18852-60
  • Peer Reviewed
• [Journal Article] HSP27 phosphorylation is correlated with ADP-induced platelet granule secretion. (2008)
  • Author(s): Kato H, Takai S, Matsushima-Nishiwaki R, Adachi S, Minamitani C, Otsuka T, Tokuda H, Akamatsu S, Doi T, Ogura S, Kozawa O
  • Journal Title: Arch Biochem Biophys 475 Pages: 80-6
  • Peer Reviewed
• [Journal Article] (-)-Epigallocatechin Gallate Suppresses Azoxymethane-Induced Colonic Premalignant Lesions in Male C57BL/KsJ-db/db Mice. (2008)
  • Author(s): Shimizu M, Shirakami Y, Sakai H, Adachi S, Hata K, Hirose Y, Tsurumi H, Tanaka T, Moriwaki H
  • Journal Title: Cancer Prev Res 1 Pages: 298-304
  • Peer Reviewed
• [Journal Article] (-)-Epigallocatechin Gallate Causes Internalization of the Epidermal Growth Factor Receptor in human colon cancer cells. (2008)
  • Author(s): Adachi S, Nagao T, To S, Joe AK, Shimizu M, Matsushima-Nishiwaki R, Kozawa O, Moriwaki H, Maxfield FR, Weinstein IB
  • Journal Title: Carcinogenesis 29 Pages: 1986-93
  • Peer Reviewed
• [Journal Article] Cytotoxic chalcones and antioxidants from the fruits of Syzygium samarangense (Wax Jambu). (2008)
  • Author(s): Simirgiotis MJ, Adachi S, To S, Yang H, Reynertson KA, Basile MJ, Gil RR, Weinstein IB, Kennelly EJ
  • Journal Title: Food Chemistry 107 Pages: 813-819
  • Peer Reviewed
• [Journal Article] (-)-Epigallocatechin gallate causes internalization of the epidermal growth factor receptor in human colon cancer cells (2008)
  • Author(s): Adachi S, et.al.
  • Journal Title: Carcinogenesis 29 Pages: 1986-1993
  • Peer Reviewed
• [Presentation] ワークショップ4緑茶カテキンの大腸癌細胞増殖抑制の新規メカニズム～脂質ラフトでのEGFR pathwayの阻害～足立政治 (2008)
  • Author(s): I. Bernard Weinstein, 森脇久隆
  • Organizer: 第94回日本消化器病学会総会
  • Place of Presentation: 福岡
  • Year and Date: 2008-05-08
• [Presentation] (-)-Epigallocatechin Gallate Induces Phosphorylation of the Epidermal growth factor Receptor via Activation of p38 MAPK in colon cancer cells (2008)
  • Author(s): Adachi S, et.al.
  • Organizer: American Association of Cancer Research 2008
  • Place of Presentation: San Diego (USA)
  • Year and Date: 2008-04-13
• [Presentation] (-)-Epigallocatechin Gallate Induces phosphorylation of Epidermal growth factor receptor via activation of p38 MAPK in colon cancer cells. (2008)
  • Author(s): Adachi S, To S, Shimizu M, Moriwaki H, Weinstein IB
  • Organizer: 99th AACR (American Association for Cancer Research) Annual Meeting
  • Place of Presentation: San Diego
• [Book] 緑茶カテキンの大腸癌細胞増殖抑制の新規メカニズム～脂質ラフトでのEGFR pathwayの阻害～ (2009)
  • Author(s): 足立政治, ほか
  • Total Pages: 5
  • Publisher: 医学書院