The Tumour Suppressor CYLD Is Required for Clathrin-Mediated Endocytosis of EGFR and Cetuximab-Induced Apoptosis in Head and Neck Squamous Cell Carcinoma.
The Tumour Suppressor CYLD Is Required for Clathrin-Mediated Endocytosis of EGFR and Cetuximab-Induced Apoptosis in Head and Neck Squamous Cell Carcinoma.
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DOI：
10.3390/cancers14010173
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发表时间：
2021-12-30
期刊：
影响因子：
5.2
通讯作者：
Matsui H
中科院分区：
文献类型：
--
作者：
Liu R;Shinriki S;Maeshiro M;Hirayama M;Jono H;Yoshida R;Nakayama H;Matsui H
表皮生长因子受体（EGFR）是治疗性抗体西妥昔单抗（CTX）治疗头颈部鳞状细胞癌（HNSCC）的靶点。其预测性生物标志物的鉴定和基于CTX的疗法的增强是重要的。在这项研究中，我们发现圆柱瘤病（CYLD）的N-末端部分是网格蛋白介导的内吞作用（CME）和EGFR降解所必需的。CYLD的缺失限制了EGFR在脂筏上的表达，并抑制了CTX诱导的细胞凋亡。胆固醇清除剂对脂筏的破坏恢复了CYLD下调细胞中EGFR CME和CTX的活性。我们的研究结果提供了新的见解EGFR贩运和耐药性的分子机制，并建议在HNSCC的CTX为基础的治疗联合降胆固醇药物的有用性。表皮生长因子受体（EGFR）经常在头颈部鳞状细胞癌（HNSCC）中过表达，并且是治疗性抗体西妥昔单抗（CTX）的靶点。然而，由于只有一些患者对CTX有显著的临床反应，因此鉴定其预测性生物标志物和增强基于CTX的治疗是重要的。我们最近报道了原发性HNSCC中圆柱瘤病（CYLD）的频繁下调，这导致了细胞侵袭和顺铂耐药的增加。在这里，我们表明，CYLD主要位于脂筏所需的网格蛋白介导的内吞作用（CME）和EGF和CTX诱导的EGFR在HNSCC细胞的降解。CYLD的N-末端含有第一个细胞因子相关蛋白-甘氨酸结构域，负责这种调节。CYLD的缺失将EGFR限制在脂筏上，从而抑制CTX诱导的细胞凋亡，而不妨碍CTX对下游信号通路的抑制活性。用胆固醇去除剂破坏脂筏通过恢复CME和EGFR的降解克服了这种抗性。因此，CYLD对EGFR运输的调节对于CTX的抗肿瘤活性至关重要。我们的研究结果表明，降胆固醇药物与抗EGFR抗体治疗HNSCC的组合是有用的。
Epidermal growth factor receptor (EGFR) is a target for the therapeutic antibody cetuximab (CTX) in head and neck squamous cell carcinoma (HNSCC). Identification of its predictive biomarkers and potentiation of CTX-based therapies are important. In this study, we found that the N-terminal portion of cylindromatosis (CYLD) was required for clathrin-mediated endocytosis (CME) and degradation of EGFR. Loss of CYLD limited EGFR to lipid rafts and inhibited CTX-induced apoptosis. Destruction of lipid rafts by cholesterol removers restored EGFR CME and CTX activity in CYLD-downregulated cells. Our findings provide novel insights into the molecular mechanisms underlying EGFR trafficking and resistance to CTX, and suggest the usefulness of CTX-based therapy combined with cholesterol-lowering drugs in HNSCC. Epidermal growth factor receptor (EGFR) is frequently overexpressed in head and neck squamous cell carcinoma (HNSCC) and is a target for the therapeutic antibody cetuximab (CTX). However, because only some patients have a significant clinical response to CTX, identification of its predictive biomarkers and potentiation of CTX-based therapies are important. We have recently reported a frequent downregulation of cylindromatosis (CYLD) in primary HNSCC, which led to increased cell invasion and cisplatin resistance. Here, we show that CYLD located mainly in lipid rafts was required for clathrin-mediated endocytosis (CME) and degradation of the EGFR induced by EGF and CTX in HNSCC cells. The N-terminus containing the first cytoskeleton-associated protein-glycine domain of CYLD was responsible for this regulation. Loss of CYLD restricted EGFR to lipid rafts, which suppressed CTX-induced apoptosis without impeding CTX’s inhibitory activity against downstream signalling pathways. Disruption of the lipid rafts with cholesterol-removing agents overcame this resistance by restoring CME and the degradation of EGFR. Regulation of EGFR trafficking by CYLD is thus critical for the antitumour activity of CTX. Our findings suggest the usefulness of a combination of cholesterol-lowering drugs with anti-EGFR antibody therapy in HNSCC.
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影响因子：
21.3
作者：
Lin, SY;Makino, K;Hung, MC
通讯作者：
Hung, MC
通过胆固醇封存增强 EGFR 靶向抗体西妥昔单抗和抗体药物缀合物的肿瘤摄取和治疗功效。
影响因子：
6.4
作者：
Chen, Yang;Liu, Guanghua;Luo, Yongzhang
通讯作者：
Luo, Yongzhang
EGFR 酪氨酸激酶抑制剂对头颈鳞状细胞癌自噬的影响不同
DOI：
10.1016/j.bbrc.2017.03.157
发表时间：
2017-05-13
影响因子：
3.1
作者：
Cai, Jinyang;Sun, Ming;Sun, Yue
通讯作者：
Sun, Yue
影响因子：
4
作者：
Azimifar, S. Babak;Boettcher, Ralph T.;Faessler, Reinhard
通讯作者：
Faessler, Reinhard
影响因子：
3.7
作者：
Jaramillo, Maria L.;Leon, Zully;McCourt, Maureen O'Connor
通讯作者：
McCourt, Maureen O'Connor