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.

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 (Z15, Z114 and Z277) 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, Z277 showed higher antitumor efficacy than Z15 and Z114 affibody molecules. The ability of Z277 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 Z277 and caused no apparent toxicity. Taken together, our findings provide evidence that Z277 as a promising therapeutic agent in EBV-associated NPC.