Maytansine Inhibits Epithelial-mesenchymal Transition In Nasopharyngeal Carcinoma Cells And Its Potential Mechanism

Nasopharyngeal carcinoma(NPC)is a common type of malignancy in south China.Radiotherapy or chemoradiotherapy has become the primary treatment for early or locoregionally advanced nasopharyngeal carcinoma,producing a 5 year survival rate of about 85%.However,the great potentiality of systemic dissemination remains the major reason of treatment failure for these patients.At present,cisplatin plus continuous intravenous infusion of fluorouracil is widely used in patients with recurrent or metastatic nasopharyngeal carcinoma.However,the short duration of response and common complications remain the major limitations of the fluorouracil plus cisplatin regimen.Therefore,finding new combination chemotherapies to prolong survival of patients with recurrent or metastatic nasopharyngeal carcinoma with reduction of common complications is of importance.Antibody-drug conjugates(ADCs)designed in recent years are intended to highly target and kill only the cancer cells and maytansine is a cytotoxic agent that is widely used in ADCs.In this study,the effects of maytansine on the cell biology in NPC cells will be investigated.Datasets(GSE69042)from GEO were downloaded to analyze the effects of maytansine on tumor cells.Datasets of GSE69042 consisted of 8 samples,which included 4 T-DM1 treated human breast cancer cells in mice and 4 trastuzumab treated human breast cancer cells in mice.Differentially expressed genes(DEGs)between T-DM1 treated human breast cancer cells and trastuzumab treated human breast cancer cells were identified.Interestingly,bioinformatics analysis showed that maytansine suppressed the expression of EMT associated DEGs significantly.Previous studies suggested that maytansine reversed EMT in breast cancer cells.Thus,we further investigated if maytansine reversed EMT in nasopharyngeal carcinoma.The cytotoxic effects of maytansine on NPC cell lines were first evaluated by MTT assay.It showed that maytansine significantly inhibited cell proliferation of NPC cells in both dose-and time-dependent manner.Meanwhile,Using colony formation and cell-cycle analysis,we found that maytansine significantly suppressed cell growth in vitro and induced G1 to S cell cycle arrest in NPC cells.Then the in vivo effect of maytansine was evaluated in xenograft mouse models bearing tumours originating from NPC cells,the result also suggested maytansine significantly inhibited tumorigenesis in vivo.Furthermore,wound-healing assays,Transwell migration assays and Boyden assays demonstrated that maytansine decreased the cell migration and invasion of NPC cells.Western blot showed that maytansine significantly decreased the expression of EMT associated proteins such as E-cadherin,N-cadherin and Vimentin.These results suggested that maytansine suppressed the migratory and invasive abilities via reversing EMT in NPC cells.Previous studies have demonstrated that cancer stem cells(CSCs)contributes to the therapy resistance and relapse.Thus,tumor sphere formation assays were used to analyze the effects of maytansine on the proliferation of CSCs.It showed that maytansine suppressed the proliferation of CSCs in vitro.Western blots showed that the expression of biomarkers of CSCs were suppressed in NPC.These results suggested that maytansine inhibited the migration,invasion and proliferation of CSCs in vitro via resversing EMT in NPC cells.It is well known that EMT is closely associated with cell migration and invasion as well as the biology of CSCs.Thus,we next explored the potential mechanism of reversing EMT in NPC cells by maytansine via an integrated bioinformatics analysis.The result showed that SMAD2 may play an important role in the process of reversing EMT in NPC cells by maytansine.In conclusion,we have demonstrated that maytansine inhibited NPC cell proliferation in vitro and in vivo.Furthermore,we have suggested that maytansine suppressed NPC cell migration and invastion via reversing EMT and maytansine may reverse EMT in NPC cells by inhibiting SMAD2 signaling pathway.Thus,these results support maytansine as a promising therapeutic agent in the treatment of NPC.