EGCG inhibits activation of the insulin-like growth factor (IGF)/IGF-1 receptor axis in human hepatocellular carcinoma cells

Shimizu, Masahito; Shirakami, Yohei; Sakai, Hidetaka; Tatebe, Hideharu; Nakagawa, Takayuki; Hara, Yukihiko; Weinstein, I. Bernard; Moriwaki, Hisataka

doi:10.1016/j.canlet.2007.11.026

Cited by 113 publications

(98 citation statements)

References 31 publications

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“…Phosphorylation of AKT at Ser473 in SMMC7721 cells was reduced by EGCG (Fig. 5), which was consistent with a previous study of HepG2 cells, reporting that EGCG induced apoptosis and caused a decrease in the p-IGF-1R protein and its downstream signaling molecules including the p-ERK, p-Akt, p-Stat-3, and p-GSK-3β proteins (29).…”

Section: Discussionsupporting

confidence: 92%

Epigallocatechin-3-gallate inhibits cell growth, induces apoptosis and causes S phase arrest in hepatocellular carcinoma by suppressing the AKT pathway

Shen

Zhang

Yan

et al. 2014

International Journal of Oncology

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Abstract. Epigallocatechin-3-gallate (EGCG) has been shown to inhibit the growth and induce apoptosis of certain cancer cells. The aim of this study was to determine the role of EGCG in hepatocellular carcinoma (HCC) and the underlying mechanism(s) thereof. MTT assay was used to determine the cell growth inhibition by EGCG. Apoptosis induced by EGCG was investigated by both AO/EB staining and flow cytometry. The cell cycle distribution was analyzed by flow cytometry. The mRNA levels of the AKT pathway were analyzed by quantitative PCR. The expression of AKT and its phosphorylation at Ser473 were detected by western blotting. The IC 50 of EGCG at 48 h for HepG2, SMMC7721 and SK-hep1 cells were 74.7, 59.6 and 61.3 µg/ml, respectively. Significantly higher proportion of SMMC7721 cells entered the S phase upon treatment with EGCG for 48 h compared with control cells. EGCG decreased the mRNA levels of PI3K, AKT and NF-κB. The protein levels of AKT decreased and its phosphorylation at Ser473 was downregulated with EGCG treatment. EGCG inhibited growth by affecting the cell cycle and induced apoptosis in different HCC cells by downregulating PI3K/ AKT activity. The results suggest the potential of EGCG as an anticancer agent in the prevention or treatment of HCC.

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Section: Discussionsupporting

confidence: 92%

Epigallocatechin-3-gallate inhibits cell growth, induces apoptosis and causes S phase arrest in hepatocellular carcinoma by suppressing the AKT pathway

Shen

Zhang

Yan

et al. 2014

International Journal of Oncology

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“…Similar effects of GTCs have been observed towards IGF-R1 [74]. IGF-R1 is overexpressed in PCa [67].…”

Section: Cell Surface Receptorssupporting

confidence: 76%

Green Tea Catechins for Prostate Cancer Prevention: Present Achievements and Future Challenges

Naponelli¹,

Ramazzina²,

Lenzi³

et al. 2017

Preprint

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Green Tea Catechins (GTCs) are a family of chemically related compounds usually classified as antioxidant molecules. Epidemiological evidences, supported by interventional studies, highlighted a more than promising role for GTCs in human Prostate Cancer (PCa) chemoprevention.In the last decades many efforts have been made to gain new insights into the mechanism of action of GTCs. Now it is clear that GTCs anticancer action can no longer be simplistically limited to their direct antioxidant/pro-oxidant properties. Recent contributions to the advancement of knowledge in this field have shown that GTCs specifically interact with cellular targets including, cell surface receptors, lipid rafts and endoplasmic reticulum, modulate gene expression through direct effect on transcription factors or indirect epigenetic mechanisms, interfere with intracellular proteostasis at various levels. Many of the effects observed in vitro are dose and cell context dependent and take place at concentration that cannot be achieved in vivo.Poor intestinal absorption together with an extensive systemic and enteric metabolism influence GTCs bioavailability through still poor understood mechanisms. Recent efforts to develop delivery systems that increase GTCs overall bioavailability, by mean of biopolymeric nanoparticles, represent the main way to translate preclinical results in a real clinical scenario for PCa chemoprevention.

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“…These findings seem to be significant because the alteration of the IGF/ IGF-1R axis, which is induced by insulin resistance, is involved in liver carcinogenesis and thus might play a critical role as a molecular target for HCC chemoprevention (6)(7)(8). In human HCC-derived cells, IGF-1 and IGF-2 activate IGF-1R, ERK, and Akt proteins and increase the expression of IGF-1 and IGF-2 mRNAs themselves but EGCG inhibits these sequences and thus suppresses growth and induces apoptosis in HCC cells (13). These findings, together with the results of the present study, suggest the possibility that EGCG overcomes the stimulatory effects of IGFs, disrupts the IGF/IGF-1R-related autocrine/paracrine loops, and thereby prevents the development of obesityrelated liver tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

“…Among such RTKs, the IGF-1R is one of the critical targets of EGCG with respect to its anticancer effects. In human HCC-and colon cancer-derived cells, EGCG suppresses cell growth by inhibiting the activation of the IGF/ IGF-1R axis and its downstream ERK (extracellular signalregulated kinase) and Akt proteins (13)(14)(15). EGCG also overcomes the activation of the IGF/IGF-1R axis and thereby inhibits the development of colonic premalignant lesions in an obesity-related colon carcinogenesis model (16).…”

Section: Introductionmentioning

confidence: 99%

Preventive Effects of (−)-Epigallocatechin Gallate on Diethylnitrosamine-Induced Liver Tumorigenesis in Obese and Diabetic C57BL/KsJ-db/db Mice

Shimizu

Sakai²,

Shirakami³

et al. 2011

Cancer Prevention Research

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Obesity and related metabolic abnormalities, including insulin resistance and a state of chronic inflammation, increase the risk of hepatocellular carcinoma. Abnormal activation of the insulin-like growth factor (IGF)/ IGF-1 receptor (IGF-1R) axis is also involved in obesity-related liver tumorigenesis. In the present study, we examined the effects of (À)-epigallocatechin gallate (EGCG), a major biologically active component of green tea, on the development of diethylnitrosamine (DEN)-induced liver tumorigenesis in C57BL/KsJ-db/db (db/db) obese mice. Male db/db mice were given tap water containing 40 ppm DEN for 2 weeks and then they received drinking water containing 0.1% EGCG for 34 weeks. At sacrifice, drinking water with EGCG significantly inhibited the development of liver cell adenomas in comparison with the control EGCG-untreated group. EGCG inhibited the phosphorylation of the IGF-1R, ERK (extracellular signal-regulated kinase), Akt, GSK-3b (glycogen synthase kinase-3b), Stat3, and JNK (c-Jun NH 2 -terminal kinase) proteins in the livers of experimental mice. The serum levels of insulin, IGF-1, IGF-2, free fatty acid, and TNF-a were all decreased by drinking EGCG, which also decreased the expression of TNF-a, interleukin (IL)-6, IL-1b, and IL-18 mRNAs in the livers. In addition, EGCG improved liver steatosis and activated the AMP-activated kinase protein in the liver. These findings suggest that EGCG prevents obesity-related liver tumorigenesis by inhibiting the IGF/IGF-1R axis, improving hyperinsulinemia, and attenuating chronic inflammation. EGCG, therefore, may be useful in the chemoprevention of liver tumorigenesis in obese individuals. Cancer Prev Res; 4(3); 396-403. Ó2011 AACR.

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EGCG inhibits activation of the insulin-like growth factor (IGF)/IGF-1 receptor axis in human hepatocellular carcinoma cells

Cited by 113 publications

References 31 publications

Epigallocatechin-3-gallate inhibits cell growth, induces apoptosis and causes S phase arrest in hepatocellular carcinoma by suppressing the AKT pathway

Epigallocatechin-3-gallate inhibits cell growth, induces apoptosis and causes S phase arrest in hepatocellular carcinoma by suppressing the AKT pathway

Green Tea Catechins for Prostate Cancer Prevention: Present Achievements and Future Challenges

Preventive Effects of (−)-Epigallocatechin Gallate on Diethylnitrosamine-Induced Liver Tumorigenesis in Obese and Diabetic C57BL/KsJ-db/db Mice

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