Cereblon upregulation overcomes thalidomide resistance in multiple myeloma through mitochondrial functional...

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Multiple myeloma patients often develop resistance to thalidomide, a crucial therapy.
• The underlying mechanisms of thalidomide resistance and effective countermeasures are not fully understood.

Purpose of the Study:

• To investigate the role of cereblon (CRBN) and mitochondrial function in overcoming thalidomide resistance in multiple myeloma.
• To explore CRBN as a therapeutic target for enhancing thalidomide efficacy.

Main Methods:

• In vitro studies using multiple myeloma cell lines (KSM20, KMS26) to assess cell viability, mitochondrial function (ATP, membrane potential, ROS), and protein expression.
• In vivo xenograft mouse models to evaluate the impact of CRBN modulation on tumor growth and survival.
• Genetic manipulation (CRBN overexpression/knockdown) and pharmacological treatments were employed.

Main Results:

• CRBN overexpression in thalidomide-resistant KMS20 cells reversed resistance, reduced tumor growth, and improved survival in mice.
• CRBN knockdown in thalidomide-sensitive KMS26 cells induced resistance.
• CRBN modulation influenced mitochondrial function and protein expression, mediated by AMPKα1 signaling, leading to cell death.

Conclusions:

• Cereblon (CRBN) levels directly impact mitochondrial function and sensitivity to thalidomide in multiple myeloma.
• Targeting cereblon presents a promising strategy to overcome thalidomide resistance by reprogramming mitochondrial pathways.
• Modulating CRBN offers a potential therapeutic approach for enhancing thalidomide treatment in multiple myeloma.