Identification of early growth response protein 1 (EGR-1) as a novel target for JUN-induced apoptosis in multiple myeloma.
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.
Chen
Lijuan
L
The 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.
Wang
Siqing
S
Zhou
Yiming
Y
Wu
Xiaosong
X
Entin
Igor
I
Epstein
Joshua
J
Yaccoby
Shmuel
S
Xiong
Wei
W
Barlogie
Bart
B
Shaughnessy
John D
JD
Zhan
Fenghuang
F
D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism; D010641:Phenotype; D010950:Plasma Cells / Q000187:drug effects / Q000378:metabolism; D011379:Prognosis; D011485:Protein Binding / Q000187:drug effects; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology; D012307:Risk Factors; D015398:Signal Transduction / Q000187:drug effects; D000077022:Survivin
C107489:BIRC5 protein, human; D001897:Boronic Acids; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D016755:Proto-Oncogene Proteins c-jun; D011719:Pyrazines; D000077022:Survivin; D000069286:Bortezomib