Increased signaling through p62 in the marrow microenvironment increases myeloma cell growth and osteoclast formation.
Adhesive interactions between multiple myeloma (MM) cells and marrow stromal cells activate multiple signaling pathways including nuclear factor kappaB (NF-kappaB), p38 mitogen-activated protein kinase (MAPK), and Jun N-terminal kinase (JNK) in stromal cells, which promote tumor growth and bone destruction. Sequestosome-1 (p62), an adapter protein that has no intrinsic enzymatic activity, serves as a platform to facilitate formation of signaling complexes for these pathways. Therefore, we determined if targeting only p62 would inhibit multiple signaling pathways activated in the MM microenvironment and thereby decrease MM cell growth and osteoclast formation. Signaling through NF-kappaB and p38 MAPK was increased in primary stromal cells from MM patients. Increased interleukin-6 (IL-6) production by MM stromal cells was p38 MAPK-dependent while increased vascular cell adhesion molecule-1 (VCAM-1) expression was NF-kappaB-dependent. Knocking-down p62 in patient-derived stromal cells significantly decreased protein kinase Czeta (PKCzeta), VCAM-1, and IL-6 levels as well as decreased stromal cell support of MM cell growth. Similarly, marrow stromal cells from p62(-/-) mice produced much lower levels of IL-6, tumor necrosis factor-alpha (TNF-alpha), and receptor activator of NF-kappaB ligand (RANKL) and supported MM cell growth and osteoclast formation to a much lower extent than normal cells. Thus, p62 is an attractive therapeutic target for MM.
Hiruma
Yuko
Y
Medicine/Hem-Onc, University of Pittsburgh, PA, USA.
Honjo
Tadashi
T
Jelinek
Diane F
DF
Windle
Jolene J
JJ
Shin
Jaekyoon
J
Roodman
G David
GD
Kurihara
Noriyoshi
N
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism* / Q000473:pathology / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D004777:Environment; D005260:Female; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010010:Osteoclasts / Q000378:metabolism / Q000502:physiology*; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D006360:Heat-Shock Proteins; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse