The oxidative stress response regulates DKK1 expression through the JNK signaling cascade in multiple myeloma plasma cells.
Multiple myeloma (MM) plasma cells, but not those from healthy donors and patients with monoclonal gammopathy of undetermined significance or other plasma cell dyscrasias involving the bone marrow, express the Wnt-signaling antagonist DKK1. We previously reported that secretion of DKK1 by MM cells likely contributes to osteolytic lesions in this disease by inhibiting Wnt signaling, which is essential for osteoblast differentiation and survival. The mechanisms responsible for activation and regulation of DKK1 expression in MM are not known. Herein, we could trace DKK1 expression changes in MM cells to perturbations in the JNK signaling cascade, which is differentially modulated through oxidative stress and interactions between MM cells with osteoclasts in vitro. Despite its role as a tumor suppressor and mediator of apoptosis in other cell types including osteoblasts, our data suggest that DKK1, a stress-responsive gene in MM, does not mediate apoptotic signaling, is not activated by TP53, and its forced overexpression could not inhibit cell growth or sensitize MM cells to apoptosis following treatment with thalidomide or lenalidomide. We conclude that specific strategies to modulate persistent activation of the JNK pathway may be beneficial in preventing disease progression and treating myeloma-associated bone disease by inhibiting DKK1 expression.
Colla
Simona
S
Donna D. and Donald M. Lambert Laboratory of Myeloma Genetics at the Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Zhan
Fenghuang
F
Xiong
Wei
W
Wu
Xiaosong
X
Xu
Hongwei
H
Stephens
Owen
O
Yaccoby
Shmuel
S
Epstein
Joshua
J
Barlogie
Bart
B
Shaughnessy
John D
JD
D000970:Antineoplastic Agents / Q000494:pharmacology; D002478:Cells, Cultured; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D000077269:Lenalidomide; D008954:Models, Biological; D009101:Multiple Myeloma / Q000235:genetics* / Q000473:pathology; D010010:Osteoclasts / Q000378:metabolism / Q000502:physiology; D018384:Oxidative Stress / Q000502:physiology*; D010950:Plasma Cells / Q000187:drug effects / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000502:physiology; D015398:Signal Transduction; D013792:Thalidomide / Q000031:analogs & derivatives / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
D000970:Antineoplastic Agents; C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D016755:Proto-Oncogene Proteins c-jun; D016159:Tumor Suppressor Protein p53; D013792:Thalidomide; D048031:JNK Mitogen-Activated Protein Kinases; D000077269:Lenalidomide