Mechanistic Studies and a Retrospective Cohort Study: The Interaction between PPAR Agonists and Immunomodulatory
Jian Wu1, Emily Chu1, Barry Paul1
1Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
Abstract:
Our previous study demonstrated that peroxisome proliferator-activated receptor (PPAR) agonists downregulated cereblon (CRBN) expression and reduced the anti-myeloma activity of lenalidomide in vitro and in vivo. We aimed to determine whether DNA methylation and protein degradation contribute to the effects of PPAR agonists. CRBN promoter methylation status was detected using methylation-specific polymerase chain reaction. The CRBN protein degradation rate was measured using a cycloheximide chase assay. Metabolomic analysis was performed in multiple myeloma (MM) cells treated with PPAR agonists and/or lenalidomide. Our retrospective study determined the effect of co-administration of PPAR agonists with immunomodulatory drugs on the outcomes of patients with MM. CpG islands of the CRBN promoter region became highly methylated upon treatment with PPAR agonists, whereas treatment with PPAR antagonists resulted in unmethylation. The CRBN protein was rapidly degraded after treatment with PPAR agonists. Lenalidomide and fenofibrate showed opposite effects on acylcarnitines and amino acids. Co-administration of immunomodulatory drugs and PPAR agonists was associated with inferior treatment responses and poor survival. Our study provides the first evidence that PPAR agonists reduce CRBN expression through various mechanisms including inducing methylation of CRBN promoter CpG island, enhancing CRBN protein degradation, and affecting metabolomics of MM cells.
Insights
Peroxisome proliferator-activated receptor (PPAR) agonists reduce cereblon (CRBN) expression in multiple myeloma cells by increasing DNA methylation and protein degradation. This mechanism impairs lenalidomide
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Previous studies showed PPAR agonists decrease cereblon (CRBN) expression, reducing lenalidomide's anti-myeloma effects.
- The mechanisms underlying PPAR agonist-induced CRBN downregulation were not fully understood.
Purpose of the Study:
- To investigate the roles of DNA methylation and protein degradation in PPAR agonist-mediated CRBN downregulation.
- To explore the impact of PPAR agonists on the metabolomics of multiple myeloma cells.
- To evaluate the clinical outcomes of co-administering PPAR agonists with immunomodulatory drugs in multiple myeloma patients.
Main Methods:
- Methylation-specific polymerase chain reaction to assess CRBN promoter methylation.
- Cycloheximide chase assay to measure CRBN protein degradation rates.
- Metabolomic analysis of multiple myeloma cells treated with PPAR agonists and/or lenalidomide.
- Retrospective analysis of patient data for co-administration outcomes.
Main Results:
- PPAR agonists induced significant methylation of the CRBN promoter CpG island.
- PPAR agonists accelerated CRBN protein degradation.
- Distinct metabolic profiles were observed with lenalidomide and fenofibrate treatment.
- Co-administration of immunomodulatory drugs and PPAR agonists correlated with poorer treatment response and survival in multiple myeloma patients.
Conclusions:
- PPAR agonists reduce CRBN expression via epigenetic modification (CpG island methylation) and enhanced protein degradation.
- PPAR agonists alter the metabolomics of multiple myeloma cells.
- Combined use of immunomodulatory drugs and PPAR agonists in multiple myeloma patients is associated with adverse outcomes.
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