ERRγ Promotes Multiple Myeloma Survival by Coordinating NF-κB Signaling and Mitochondrial Apoptosis Regulation
Xiaobing Zhou1, Ying Li2, Zizi Jing1
1Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
Background:
Multiple myeloma (MM) remains a formidable clinical challenge due to its high relapse rate and resistance to existing therapies. Estrogen-related receptor gamma (ERRγ), a nuclear receptor critical for cellular energy metabolism, has been implicated in various cancers. but its role in MM remains unclear.
Methods:
ERRγ expression was assessed using bioinformatics and RT-qPCR. Functional studies were conducted through siRNA-mediated ERRγ knockdown and treatment with the inverse agonist GSK5182 to examine their effects on MM cell proliferation and apoptosis.
Results:
ERRγ was significantly upregulated in the bone marrow of MM patients, correlating with advanced clinical stages and pathological fractures. Inhibition of ERRγ reduced MM cell expansion both in vitro and in vivo, while promoting mitochondrial-dependent apoptosis. Co-immunoprecipitation assays demonstrated a physical association between ERRγ and P65. Inhibition of ERRγ attenuated canonical nuclear factor-kappa B (NF-κB) signaling by blocking the nuclear translocation of its key effector p65. Additionally, modulation of ERRγ altered receptor activator of nuclear factor-κB ligand (RANKL) levels, implying a potential role in bone degradation observed in MM cases.
Conclusion:
Collectively, the data broaden understanding of ERRγ's contribution to MM development and propose it as a viable target for therapeutic intervention.
Insights
Estrogen-related receptor gamma (ERRγ) is upregulated in multiple myeloma (MM) and drives cancer growth. Inhibiting ERRγ may offer a new therapeutic strategy for MM patients.
Area of Science:
- Oncology
- Molecular Biology
- Cell Metabolism
Background:
- Multiple myeloma (MM) presents significant therapeutic challenges due to high relapse rates and treatment resistance.
- Estrogen-related receptor gamma (ERRγ), a key regulator of cellular metabolism, has roles in various cancers, but its function in MM is not well understood.
Purpose of the Study:
- To investigate the role of ERRγ in the development and progression of multiple myeloma.
- To explore the potential of targeting ERRγ as a therapeutic strategy for MM.
Main Methods:
- Bioinformatic analysis and quantitative reverse transcription PCR (RT-qPCR) were used to assess ERRγ expression.
- Functional studies involved siRNA-mediated knockdown of ERRγ and treatment with the inverse agonist GSK5182.
- Cellular proliferation, apoptosis, and signaling pathways (NF-κB, RANKL) were analyzed.
Main Results:
- ERRγ expression was significantly elevated in the bone marrow of MM patients, correlating with disease stage and bone complications.
- ERRγ inhibition suppressed MM cell proliferation in vitro and in vivo, inducing mitochondrial-dependent apoptosis.
- ERRγ physically interacted with P65, attenuating NF-κB signaling and altering RANKL levels, suggesting a role in MM-related bone degradation.
Conclusions:
- The findings highlight ERRγ's significant contribution to MM pathogenesis.
- ERRγ represents a promising therapeutic target for overcoming MM resistance and improving patient outcomes.
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