The Downregulation of eIF3a Contributes to Vemurafenib Resistance in Melanoma by Activating ERK via PPP2R1B.

Shi-Long Jiang,Yan Cheng,Ting Jiang,Zhao-Qian Liu,Tao Zhu,Chong Liu,Zhi-Bin Wang,Chao Luo,Jiang-Feng Fei

doi:10.3389/fphar.2021.720619

Abstract

Vemurafenib, a BRAF V600E inhibitor, provides therapeutic benefits for patients with melanoma, but the frequent emergence of drug resistance remains a challenge. An understanding of the mechanisms underlying vemurafenib resistance may generate novel therapeutic strategies for patients with melanoma. Here, we showed that eIF3a, a translational regulatory protein, was an important mediator involved in vemurafenib resistance. eIF3a was expressed at significantly lower levels in vemurafenib-resistant A375 melanoma cells (A375R) than in parental A375 cells. Overexpression of eIF3a enhanced the sensitivity to BRAF inhibitors by reducing p-ERK levels. Furthermore, eIF3a controlled ERK activity by regulating the expression of the phosphatase PPP2R1B via a translation mechanism, thus determining the sensitivity of melanoma cells to vemurafenib. In addition, a positive correlation between eIF3a and PPP2R1B expression was also observed in tumor samples from the Human Protein Atlas and TCGA databases. In conclusion, our studies reveal a previously unknown molecular mechanism of BRAF inhibitor resistance, which may provide a new strategy for predicting vemurafenib responses in clinical treatment.

Highlights

Melanoma is an aggressive cancer with a rapidly increasing incidence (Bellmann et al, 2020)
SiRNA-mediated knockdown of Eukaryotic translation initiation factor 3a (eIF3a) decreased the responses of human melanoma cells to vemurafenib, as evidenced by the results of the CCK8 assay and colony formation assay (Figures 1D,E)
These data suggest that the reduced expression of eIF3a in melanoma may result in vemurafenib resistance

Summary

Introduction

Melanoma is an aggressive cancer with a rapidly increasing incidence (Bellmann et al, 2020). 60% of melanoma patients harbored BRAF kinase mutation (BRAFV600E), which activates the MAPK pathway and contributes to the immortalization of cancer (Betancourt et al, 2019). Downregulation eIF3a Contributes to Vemurafenib-Resistance dacarbazine (Chapman et al, 2011; Kim and Cohen, 2016; Chapman et al, 2017). The universal emergence of resistance after vemurafenib treatment limits its application in the clinic (Sosman et al, 2012; Sullivan and Flaherty, 2013; Samatar and Poulikakos, 2014; Garbe and Eigentler, 2018). Multiple mechanisms involved in vemurafenib resistance have been identified (Sullivan and Flaherty, 2013); these mechanisms do not fully characterize the causes of vemurafenib resistance, and effective targets and strategies for overcoming clinical vemurafenib resistance are lacking, encouraging further research (Rizos et al, 2014)

Methods

Results

Conclusion