Depletion of RBMS1 alleviates oxaliplatin chemoresistance in gastric cancer cells by suppressing the efflux function of ABCB1

Abstract

Despite its declining overall incidence, gastric cancer (GC) remains a major global health challenge as the third leading cause of cancer-related mortality. In particular, the prognosis for advanced GC patients is quite unsatisfactory, largely due to the development of chemoresistance. Here, we report that depletion of RNA Binding Motif Single Stranded Interacting Protein 1 (RBMS1) may sensitize gastric cancer cells to oxaliplatin (OXA) in multiple GC cell lines through suppressing the efflux function of ATP Binding Cassette Subfamily B Member 1 (ABCB1). By analyzing The Cancer Genome Atlas (TCGA) datasets in public databases, we found the expression of RBMS1 increased significantly with tumor progression, and positively correlated with ABCB1. By using AGS and MKN45 cells as in vitro models, we found that depletion of RBMS1 significantly decreased IC50 of OXA from 8.96 μM to 4.33 μM in AGS cells, and from 18.35 μM to 9.88 μM in MKN45 cells. Moreover, depletion of RBMS1 significantly suppressed the protein expression of ABCB1, while ectopic overexpression of RBMS1 promoted the protein expression of ABCB1. Mechanistically, RBMS1 could directly bind to the 3’ untranslated region (3’ UTR) of ABCB1 transcripts, and increase the recruitment of ABCB1 transcripts to eIF3 translation initiation complexes. Furthermore, depletion of RBMS1 also resulted in down-regulation of the mitochondrial expression of ATP synthases (ATP5B and ATP5H), leading to impaired mitochondrial respiratory function and consequent reduction in ATP production. In conclusion, these findings highlight RBMS1/ABCB1 axis as a novel target that may inform novel strategies to overcome chemoresistance for GC patients.