Blockade of deubiquitylating enzyme Rpn11 triggers apoptosis in multiple myeloma cells and overcomes bortezomib resistance

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Proteasome inhibitors are effective for multiple myeloma (MM), but drug resistance is a significant clinical challenge.
• Novel strategies are required to overcome resistance to proteasome inhibitor therapies in MM patients.

Purpose of the Study:

• To investigate if targeting deubiquitylating (DUB) enzymes upstream of the 20S proteasome can overcome proteasome inhibitor resistance in MM.
• To evaluate the therapeutic potential of inhibiting the DUB enzyme Rpn11 in MM.

Main Methods:

• Gene expression analysis, immunohistochemistry, RT-PCR, and protein analysis were used to assess Rpn11 expression in MM cells.
• Loss-of-function studies using Rpn11-siRNA and pharmacological inhibition with O-phenanthroline (OPA) were performed.
• MM cell viability, apoptosis, caspase cascade, endoplasmic reticulum stress response, and xenograft models were evaluated.
• Synergistic effects with standard anti-MM agents were assessed.

Main Results:

• Rpn11 is overexpressed in MM patient cells and correlates with poor survival.
• Rpn11 knockdown or OPA treatment reduced MM cell viability and induced apoptosis.
• OPA treatment blocked proteasome function, activated stress responses, and overcame bortezomib resistance.
• OPA reduced tumor growth and prolonged survival in MM xenograft models.
• Rpn11 blockade enhanced the cytotoxicity of lenalidomide, pomalidomide, and dexamethasone.

Conclusions:

• Rpn11 is a promising therapeutic target for overcoming proteasome inhibitor resistance in multiple myeloma.
• Targeting Rpn11 upstream of the 20S proteasome offers a novel strategy to enhance MM cell cytotoxicity.
• Preclinical data support the clinical investigation of Rpn11 inhibitors in MM treatment strategies.