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

• Published in: Frontiers in cellular and infection microbiology Vol. 12; p. 1078504
• Main Authors: Guo, Yanru, Kamara, Saidu, Zhang, Jing, Wen, He, Zheng, Maolin, Liu, Ying, Zhou, Luqi, Chen, Jun, Zhu, Shanli, Zhang, Lifang
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 04.01.2023
• Subjects: affibody molecules; Animals; Cell Line, Tumor; Cell Proliferation; Cellular and Infection Microbiology; EBV; Epstein-Barr Virus Infections - drug therapy; Herpesvirus 4, Human - metabolism; Humans; LMP1; MAP Kinase Signaling System; Mice; Mitogen-Activated Protein Kinase Kinases - metabolism; nasopharyngeal carcinoma; Nasopharyngeal Carcinoma - drug therapy; Nasopharyngeal Carcinoma - virology; Nasopharyngeal Neoplasms - drug therapy; Nasopharyngeal Neoplasms - virology; Neoplasm Recurrence, Local; Ribosomal Protein S6 Kinases, 90-kDa - metabolism; Ribosomal Protein S6 Kinases, 90-kDa - pharmacology; Ribosomal Protein S6 Kinases, 90-kDa - therapeutic use; targeted therapy; Xenograft Model Antitumor Assays; EBV; LMP1; targeted therapy; affibody molecules; nasopharyngeal carcinoma
• ISSN: 2235-2988; 2235-2988
• DOI: 10.3389/fcimb.2022.1078504

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 Z affibody molecules (Z 15, Z 114 and Z 277) that showed specific binding interactions for recombinant and native EBV LMP1 as determined by epitope mapping, co-localization and co-immunoprecipitation assays. The Z affibody molecules exhibited high antitumor effects on EBV-positive NPC cell lines and displayed minimal cytotoxicity towards EBV-negative NPC cell line. Moreover, Z 277 showed higher antitumor efficacy than Z 15 and Z 114 affibody molecules. The ability of Z 277 decrease the phosphorylation levels of up-stream activator phospho-Raf-1 , phospho-MEK1/2 , phospho-ERK1/2 , thereby leading to downstream suppression of phospho-p90RSK and transcription factor c-Fos. Importantly, tumor growth was reduced in tumor-bearing mice treated with Z 277 and caused no apparent toxicity. Taken together, our findings provide evidence that Z 277 as a promising therapeutic agent in EBV-associated NPC.