RRBP1 rewires cisplatin resistance in oral squamous cell carcinoma by regulating Hippo pathway.

Article Details

Citation

Copy to clipboard

Shriwas O, Arya R, Mohanty S, Mohapatra P, Kumar S, Rath R, Kaushik SR, Pahwa F, Murmu KC, Majumdar SKD, Muduly DK, Dixit A, Prasad P, Nanda RK, Dash R

RRBP1 rewires cisplatin resistance in oral squamous cell carcinoma by regulating Hippo pathway.

Br J Cancer. 2021 Jun;124(12):2004-2016. doi: 10.1038/s41416-021-01336-7. Epub 2021 Mar 24.

PubMed ID

33762722 [ View in PubMed

]

Abstract

BACKGROUND: Chemoresistance is one of the major factors for treatment failure in OSCC. Identifying key resistance triggering molecules will be useful strategy for developing novel treatment methods. METHODS: To identify the causative factors of chemoresistance, we performed RNA sequencing and global proteomic profiling of human OSCC lines presenting with sensitive, early and late cisplatin-resistance patterns. RESULTS: From the common set of dysregulated genes from both the analysis, RRBP1 was identified to be upregulated in both early and late cisplatin-resistant cells with respect to the sensitive counterpart. Analysis of OSCC patient sample indicates that RRBP1 expression is upregulated in chemotherapy-non-responder tumours as compared to chemotherapy-responder tumours. Genetic (knockout) or pharmacological (Radezolid, represses expression of RRBP1) inhibition of RRBP1 restores cisplatin-mediated cell death in chemo-resistant OSCC. Mechanistically, RRBP1 regulates Yes-associated protein1 (YAP1), a key protein in the Hippo pathway to induce chemoresistance. The PDC xenograft data suggests that knockout of RRBP1 induces cisplatin-mediated cell death and facilitates a significant reduction of tumour burden. CONCLUSION: Overall, our data suggests that (I) RRBP1 is a major driver of cisplatin-resistance in OSCC, (II) RRBP1 regulates YAP1 expression to mediate cisplatin-resistance, (III) Radezolid represses RRBP1 expression and (IV) targeting RRBP1 reverses cisplatin-induced chemoresistance in advanced OSCC.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Radezolid	Ribosome-binding protein 1	Protein	Humans	Unknown	Inhibitor	Details