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Sulfated galactans from red seaweed Gracilaria fisheri target epidermal growth factor receptor (EGFR) and inhibit cholangiocarcinoma cells (CCA) proliferation

机译:来自红海藻河豚的硫酸半乳聚糖靶向表皮生长因子受体(EGFR)并抑制胆管癌细胞(CCA)增殖

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摘要

Cholangiocarcinoma (CCA) is increasing in incidence worldwide and is resistant to chemotherapeutic agents, making treatment of CCA a major challenge. Previous studies reported that natural sulfated polysaccharides (SPs) disrupted growth factor receptor activation in cancer cells. The present study, therefore, aimed at investigating the anti-proliferation effect of sulfated galactans (SG) isolated from the red seaweed Gracilaria fisheri (G. fisheri) on CCA cell lines. Direct binding activity of SG to CCA cells, epidermal growth factor (EGF) and epidermal growth factor receptor (EGFR) were determined. The effect of SG on proliferation of CCA cells was investigated. Cell cycle analyses and expression of signaling molecules associated with proliferation were also determined. The results demonstrated that SG bound directly to EGFR. SG inhibited proliferation of various CCA cell lines by inhibiting EGFR and extracellular signal-regulated kinases (ERK) phosphorylation, and inhibited EGF-induced increased cell proliferation. Cell cycle analyses showed that SG induced cell cycle arrest at the G0/G1 phase, down-regulated cell cycle genes and proteins (cyclin-D, cyclin-E, Cdk-4, Cdk-2), and up-regulated the tumor suppressor protein P53 and the cyclin-dependent kinase inhibitor P21. Taken together, these data demonstrate that SG from G. fisheri inhibited proliferation of CCA cells, and its mechanism of inhibition is mediated, to some extent, by inhibitory effects on EGFR activation and EGFR/ERK signaling pathway. SG presents a potential EGFR targeted molecule, which may be further clinically developed in a combination therapy for CCA treatment.
机译:胆管癌(CCA)在世界范围内的发病率正在增加,并且对化学治疗剂具有抵抗力,这使CCA的治疗成为主要挑战。先前的研究报道,天然硫酸化多糖(SP)破坏癌细胞中的生长因子受体活化。因此,本研究旨在研究从红海藻(Gracilaria fisheri)(G。fisheri)中分离的硫酸化半乳聚糖(SG)对CCA细胞系的抗增殖作用。测定了SG与CCA细胞,表皮生长因子(EGF)和表皮生长因子受体(EGFR)的直接结合活性。研究了SG对CCA细胞增殖的影响。还确定了细胞周期分析和与增殖相关的信号分子的表达。结果表明SG直接与EGFR结合。 SG通过抑制EGFR和细胞外信号调节激酶(ERK)磷酸化来抑制各种CCA细胞系的增殖,并抑制EGF诱导的细胞增殖增加。细胞周期分析表明,SG诱导了细胞周期停滞在G0 / G1期,下调了细胞周期基因和蛋白质(cyclin-D,cyclin-E,Cdk-4,Cdk-2),并上调了肿瘤抑制因子蛋白P53和细胞周期蛋白依赖性激酶抑制剂P21。综上所述,这些数据表明来自鱼腥藻的SG抑制CCA细胞的增殖,并且其抑制机制在某种程度上是通过对EGFR激活和EGFR / ERK信号通路的抑制作用来介导的。 SG提供了潜在的EGFR靶向分子,可以在联合治疗中进一步临床开发CCA治疗药物。

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