Effects of Epidermal Growth Factor Receptor Inhibitor Genistein on Proliferative Cholangitis in Rats

Jiang, Li; Jiang, Lingjun; Yan, Lü-Nan; Li, Fuyu; Wang, Wei; Cheng, Nan‐Sheng; Wen, Tianfu

doi:10.1016/j.jss.2009.04.048

Cited by 6 publications

(7 citation statements)

References 35 publications

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“…Previous reports have shown that EGFR is involved in the proliferation and progression of CCA (31,41,42). It has been shown that GE suppresses the proliferation of proliferative cholangitis in rat models, where the expression of EGFR is high (43). Furthermore, GE conjugated with recombinant human EGF has the capability to inhibit EGFR tyrosine kinase and to trigger rapid apoptotic cell death in EGFRpositive MDA-MB231 and BT-20 breast cancer cells (44).…”

Section: Discussionmentioning

confidence: 97%

Genistein reduces the activation of AKT and EGFR, and the production of IL6 in cholangiocarcinoma cells involving estrogen and estrogen receptors

et al. 2018

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Cholangiocarcinoma (CCA) is a malignant tumor of the biliary epithelium associated with Opisthorchis viverrini, primary sclerosing cholangitis and hepatitis viral infection. In the global population, men have higher incidence rates for CCA than women; thus, a gender disparity in the progression of chronic inflammation of the biliary duct leading to malignancy may involve the effects of estrogen (E2). Genistein (GE), a prominent phytoestrogen found in soy products, is an estrogen receptor β (ERβ) agonist and a tyrosine kinase inhibitor. The present study investigated the effects of GE on the growth of CCA cells by cell viability assay. The effects on signaling proteins were detected by western blot analysis and ELISA. Gene expression was examined by RT-qPCR. Two human intrahepatic CCA cell lines, HuCCA‑1 and RMCCA‑1, were utilized. GE (50‑200 µM) reduced the viability of the two cell lines, and also inhibited the activation of epidermal growth factor receptor (EGFR) and AKT, as evidenced by decreasing protein levels of phosphorylated (p)-EGFR (Tyr1173) and p‑AKT (Ser473), respectively. GE altered the mitogen‑activated protein kinase signaling cascade by mediating decreased protein levels of p‑p38 and increased protein levels of p‑ERK1/2. GE significantly decreased the levels of interleukin 6 (IL6) and induced the expression of inducible nitric oxide synthase (iNOS). GE also downregulated the expression of p‑ERα (Ser118) protein and ERα mRNA levels. Finally, GE induced the downregulation of the protein levels of ERβ. Of note, E2 deprivation potentiated the GE-induced reduction of p‑EGFR (Tyr1173) and total AKT proteins and production of IL6, and mediated the downregulation of GE-induced iNOS protein. In conclusion, GE inhibited the growth of human CCA cell lines by reducing the activation of EGFR and AKT, and by attenuating the production of IL6. E2 and ER were also involved in the growth-inhibitory effect of GE in CCA cells.

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Section: Discussionmentioning

confidence: 97%

Genistein reduces the activation of AKT and EGFR, and the production of IL6 in cholangiocarcinoma cells involving estrogen and estrogen receptors

et al. 2018

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“…It was reported that genistein has an inhibitory effect on Epidermal Growth Factor Receptor (EGFR) and induced EGFR dimerization and down-regulation from the cell surface, and consequently inhibit EGFR signaling, leading to cell cycle arrest and/or cell death (Baselga 2001;Jiang et al 2010). Furthermore, genistein was ineffective in extracellular-signal regulated kinase (ERK) activation in EGF-stimulated cell (Croisy-Delcey et al 1997).…”

Section: Discussionmentioning

confidence: 99%

Genistein-induced G2/M cell cycle arrest of human intestinal colon cancer Caco-2 cells is associated with Cyclin B1 and Chk2 down-regulation

2013

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Genistein is an isoflavonic phyto-oestrogen contained in soya beans. It is thought to display anti-cancer effects. This study was designed to investigate its effect on human intestinal colon cancer Caco-2 cells. MTT assay, flow cytometric analysis and western blotting were used to investigate the effect of genistein on cell proliferation, cell cycle progression and protein alterations of selected cell cycle-related proteins in Caco-2 cells. Our results showed that genistein and daidzein significantly suppressed cell proliferation. Genistein treatment was demonstrated to modulate cell cycle distribution through accumulation of cells at G2/M phase, with a significant decreasing effect of Cyclin B1 and Serine/threonine-protein kinase 2 (Chk2) proteins expression. However, daidzein did not alter the cell cycle progression in Caco-2 cells. All these observation strongly indicate that genistein has anti-proliferative effect in human intestinal colon cancer Caco-2 cells through the downregulation of cell cycle check point proteins, Cyclin B1 and Chk2.

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“…Hepatolithiasis is a prevalent disease in Southeast Asia, and proliferative cholangitis (PC) serves an important role in the pathogenesis of hepatolithiasis and is correlated with ~75% of hepatolithiasis cases in Asia (1). Previously, it was confirmed that chronic PC (CPC) is a pathological foundation and the key contributor to the high recurrence rate of intrahepatic stones and biliary restenosis in patients with hepatolithiasis (2,3).…”

Section: Introductionmentioning

confidence: 99%

EGFR monoclonal antibody panitumumab inhibits chronic proliferative cholangitis by downregulating EGFR

et al. 2019

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In hepatolithiasis, chronic proliferative cholangitis (CPC), an active and longstanding inflammation of stone-containing bile ducts with enhanced mucin-producing activity, not only affects the progression of the disease, it can also induce biliary carcinogenesis. The present study aimed to examine the effect of the epidermal growth factor receptor (EGFR) monoclonal antibody panitumumab (Pani) on CPC. Following the establishment of CPC rat models, periodic acid Schiff staining was used to observe the positive rate of EGFR expression. The expression levels of EGFR, mucin 5AC (MUC5AC), Ki-67, type I collagen and mammalian target of rapamycin (mTOR), and the activity of β-glucuronidase (β-G), were measured. The rats treated with Pani demonstrated a significantly lower degree of hyperproliferation of the epithelium and submucosal glands of the bile duct and collagen fibers of the bile duct wall, a significantly decreased positive rate of EGFR, reduced phosphorylation of mTOR, decreased expression of EGFR, MUC5AC, Ki-67 and type I collagen, and reduced β-G activity. The therapeutic effects in rats treated with 4 and 6 mg/kg of Pani were more marked than those in rats treated with 2 mg/kg of Pani. Collectively, the data obtained in the present study suggest that the EGFR monoclonal antibody Pani can effectively inhibit the excessive proliferation and stone-forming potential of bile duct mucosa in CPC with a receptor saturation effect. Therefore, Pani offers promise as a treatment for the prevention and control of intra-hepatic choledocholithiasis caused by CPC.

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Effects of Epidermal Growth Factor Receptor Inhibitor Genistein on Proliferative Cholangitis in Rats

Cited by 6 publications

References 35 publications

Genistein reduces the activation of AKT and EGFR, and the production of IL6 in cholangiocarcinoma cells involving estrogen and estrogen receptors

Genistein reduces the activation of AKT and EGFR, and the production of IL6 in cholangiocarcinoma cells involving estrogen and estrogen receptors

Genistein-induced G2/M cell cycle arrest of human intestinal colon cancer Caco-2 cells is associated with Cyclin B1 and Chk2 down-regulation

EGFR monoclonal antibody panitumumab inhibits chronic proliferative cholangitis by downregulating EGFR

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