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Published on: March 27, 2020
RRBP1 rewires cisplatin resistance in oral squamous cell carcinoma by regulating Hippo pathway
Omprakash Shriwas1,2, Rakesh Arya3, Sibasish Mohanty1,4
1Institute of Life Sciences, Bhubaneswar, Odisha, India.
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.
Insights
Chemoresistance in oral squamous cell carcinoma (OSCC) is driven by RRBP1, which regulates YAP1. Inhibiting RRBP1 with Radezolid can reverse chemoresistance, offering a new treatment strategy for OSCC patients.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Chemoresistance is a significant challenge in oral squamous cell carcinoma (OSCC) treatment, leading to therapy failure.
- Identifying molecular drivers of chemoresistance is crucial for developing effective treatment strategies.
Purpose of the Study:
- To identify key molecular factors contributing to cisplatin resistance in OSCC.
- To investigate the role of RRBP1 in mediating chemoresistance and its potential as a therapeutic target.
Main Methods:
- RNA sequencing and global proteomic profiling of cisplatin-sensitive and resistant OSCC cell lines.
- Analysis of RRBP1 expression in OSCC patient tumors.
- Investigating the effect of RRBP1 inhibition (genetic or pharmacological) on chemoresistance in vitro and in vivo.
Main Results:
- RRBP1 was found to be significantly upregulated in cisplatin-resistant OSCC cells and tumors.
- Inhibition of RRBP1 restored sensitivity to cisplatin, leading to cancer cell death.
- RRBP1 was identified to regulate YAP1, a key protein in the Hippo pathway, to induce chemoresistance.
- Targeting RRBP1 significantly reduced tumor burden in preclinical models.
Conclusions:
- RRBP1 is a critical driver of cisplatin resistance in OSCC.
- RRBP1 mediates chemoresistance by regulating YAP1 expression.
- Pharmacological inhibition of RRBP1, such as with Radezolid, can reverse chemoresistance in advanced OSCC.
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