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Identification of early growth response protein 1 (EGR-1) as a novel target for JUN-induced apoptosis in multiple
Lijuan Chen1, Siqing Wang, Yiming Zhou
1The Donna D. and Donald M. Lambert Laboratory of Myeloma Genetics, Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, USA.
Abstract:
Tumor-bone marrow microenvironment interactions in multiple myeloma (MM) are documented to play crucial roles in plasma-cell growth/survival. In vitro coculture of MM cells with osteoclasts supported cell survival and significantly down-regulated JUN expression. JUN expression in myeloma cells from late-stage and high-risk MM was significantly lower than in plasma cells from healthy donors, monoclonal gammopathy of undetermined significance, smoldering MM, and low-risk MM; patients with low-JUN-expressing MM cells had earlier disease-related deaths. JUN overexpression in MM cells induced cell death and growth inhibition and up-regulated expression of early growth response protein 1 (EGR-1), whose low expression also carried unfavorable clinical implications. EGR-1 knockdown in MM cells abrogated JUN overexpression-induced MM cell death and growth inhibition, indicating that EGR-1 acts directly downstream of JUN. JUN modulates myeloma cell apoptosis through interacting with EGR-1, which down-regulates Survivin and triggers caspase signaling. Importantly, high JUN or EGR-1 expression was associated with improved outcome in Total Therapy 3, in which bortezomib is given throughout therapy, versus Total Therapy 2, in which bortezomib is given only at relapse. Consistently, JUN or EGR-1 knockdown in cultured MM cells enhanced their resistance to bortezomib, demonstrating the crucial role of low JUN/EGR-1 expression in MM resistance to bortezomib.
Insights
Low JUN and EGR-1 expression in multiple myeloma (MM) cells correlates with poor outcomes and bortezomib resistance. Upregulating JUN/EGR-1 may improve MM treatment efficacy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Interactions between multiple myeloma (MM) cells and the bone marrow microenvironment are critical for disease progression.
- JUN expression is significantly lower in advanced and high-risk MM, correlating with poorer patient outcomes.
Purpose of the Study:
- To investigate the role of JUN and early growth response protein 1 (EGR-1) in multiple myeloma cell survival, growth, and response to therapy.
- To elucidate the functional relationship between JUN and EGR-1 in MM pathogenesis.
Main Methods:
- In vitro co-culture of MM cells with osteoclasts.
- Analysis of JUN and EGR-1 expression levels in patient samples.
- JUN overexpression and EGR-1 knockdown experiments in MM cells.
- Assessment of MM cell apoptosis, growth inhibition, and response to bortezomib.
Main Results:
- Co-culture with osteoclasts down-regulated JUN expression and supported MM cell survival.
- Low JUN expression in MM cells predicted earlier disease-related death.
- JUN overexpression induced MM cell death and growth inhibition via EGR-1.
- EGR-1 knockdown abrogated JUN-induced MM cell death, confirming EGR-1 acts downstream of JUN.
- High JUN/EGR-1 expression correlated with improved outcomes in patients receiving continuous bortezomib therapy.
- JUN/EGR-1 knockdown increased MM cell resistance to bortezomib.
Conclusions:
- JUN and EGR-1 play crucial roles in regulating MM cell apoptosis and sensitivity to chemotherapy.
- Low JUN/EGR-1 expression is associated with increased resistance to bortezomib in multiple myeloma.
- Targeting JUN/EGR-1 pathways may represent a novel therapeutic strategy for overcoming bortezomib resistance in MM.
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