EBV LMP1-C terminal binding affibody molecule downregulates MEK/ERK/p90RSK pathway and inhibits the proliferation of nasopharyngeal carcinoma cells in mouse tumor xenograft models.
EBV LMP1-C terminal binding affibody molecule downregulates MEK/ERK/p90RSK pathway and inhibits the proliferation of nasopharyngeal carcinoma cells in mouse tumor xenograft models.
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DOI：
10.3389/fcimb.2022.1078504
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发表时间：
2022
影响因子：
5.7
通讯作者：
中科院分区：
文献类型：
--
作者：
鼻咽癌（Nasopharyngeal carcinoma，NPC）是一种与EB病毒（Epstein-Barr virus，EBV）相关的恶性肿瘤，最常见于中国南方和东南亚。在中国南方，它是癌症相关死亡的主要原因之一。尽管放疗和化疗技术不断改进，但局部复发和远处转移仍是鼻咽癌治疗失败的主要原因。因此，迫切需要寻找新的治疗干预的特异性药物靶点。在这里，我们报告了三个潜在的ZLMP 1-C抗体分子（ZLMP 1-C15，ZLMP 1-C114和ZLMP 1-C277），通过表位定位，共定位和免疫共沉淀测定，显示出重组和天然EBV LMP 1的特异性结合相互作用。ZLMP 1-C抗体分子对EB病毒阳性的鼻咽癌细胞株显示出高的抗肿瘤作用，对EB病毒阴性的鼻咽癌细胞株显示出最小的细胞毒性。此外，ZLMP 1-C277显示出比ZLMP 1-C15和ZLMP 1-C114抗体分子更高的抗肿瘤功效。ZLMP 1-C277能够降低上游激活剂磷酸化Raf-1（Ser 338）、磷酸化MEK 1/2（Ser 217/Ser 221）、磷酸化ERK 1/2（Thr 202/Thr 204）的磷酸化水平，从而导致磷酸化p90 RSK（Ser 380）和转录因子c-Fos的下游抑制。重要的是，用ZLMP 1-C277处理的荷瘤小鼠的肿瘤生长减少，并且没有引起明显的毒性。综上所述，我们的研究结果提供了ZLMP 1-C277作为EBV相关NPC的有希望的治疗剂的证据。
Nasopharyngeal carcinoma (NPC), is an Epstein-Barr virus (EBV) associated malignancy most common in Southern China and Southeast Asia. In southern China, it is one of the major causes of cancer-related death. Despite improvement in radiotherapy and chemotherapy techniques, locoregional recurrence and distant metastasis remains the major causes for failure of treatment in NPC patients. Therefore, finding new specific drug targets for treatment interventions are urgently needed. Here, we report three potential ZLMP1-C affibody molecules (ZLMP1-C15, ZLMP1-C114 and ZLMP1-C277) that showed specific binding interactions for recombinant and native EBV LMP1 as determined by epitope mapping, co-localization and co-immunoprecipitation assays. The ZLMP1-C affibody molecules exhibited high antitumor effects on EBV-positive NPC cell lines and displayed minimal cytotoxicity towards EBV-negative NPC cell line. Moreover, ZLMP1-C277 showed higher antitumor efficacy than ZLMP1-C15 and ZLMP1-C114 affibody molecules. The ability of ZLMP1-C277 decrease the phosphorylation levels of up-stream activator phospho-Raf-1(Ser338), phospho-MEK1/2(Ser217/Ser221), phospho-ERK1/2(Thr202/Thr204), thereby leading to downstream suppression of phospho-p90RSK(Ser380) and transcription factor c-Fos. Importantly, tumor growth was reduced in tumor-bearing mice treated with ZLMP1-C277 and caused no apparent toxicity. Taken together, our findings provide evidence that ZLMP1-C277 as a promising therapeutic agent in EBV-associated NPC.
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影响因子：
4.3
作者：
Kanakry, Jennifer A.;Ambinder, Richard F.
通讯作者：
Ambinder, Richard F.
影响因子：
3.7
作者：
Malm M;Kronqvist N;Lindberg H;Gudmundsdotter L;Bass T;Frejd FY;Höidén-Guthenberg I;Varasteh Z;Orlova A;Tolmachev V;Ståhl S;Löfblom J
通讯作者：
Löfblom J
DOI：
10.1093/protein/8.6.601
发表时间：
1995-06-01
期刊：
PROTEIN ENGINEERING
影响因子：
--
作者：
NORD, K;NILSSON, J;NYGREN, PA
通讯作者：
NYGREN, PA
影响因子：
5.8
作者：
Luo Y;Liu Y;Wang C;Gan R
通讯作者：
Gan R
影响因子：
12.8
作者：
Frejd FY;Kim KT
通讯作者：
Kim KT