Increased signaling through p62 in the marrow microenvironment increases myeloma cell growth and osteoclast formation

Yuko Hiruma, Tadashi Honjo, Diane F. Jelinek, Jolene J. Windle, Jaekyoon Shin, G. David Roodman, Noriyoshi Kurihara

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Adhesive interactions between multiple myeloma (MM) cells and marrow stromal cells activate multiple signaling pathways including nuclear factor κB (NF-κB), 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-κB 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-κB-dependent. Knocking-down p62 in patient-derived stromal cells significantly decreased protein kinase Cζ (PKCζ), 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-α (TNF-α), and receptor activator of NF-κB 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.

Original languageEnglish (US)
Pages (from-to)4894-4902
Number of pages9
JournalBlood
Volume113
Issue number20
DOIs
StatePublished - 2009
Externally publishedYes

Fingerprint

Cell growth
Osteoclasts
Multiple Myeloma
Stromal Cells
p38 Mitogen-Activated Protein Kinases
Bone Marrow
Interleukin-6
Vascular Cell Adhesion Molecule-1
Growth
Tumor Necrosis Factor Receptors
Protein Kinase C
Tumors
Adhesives
Bone
Phosphotransferases
Ligands
Bone Development
Proteins

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Increased signaling through p62 in the marrow microenvironment increases myeloma cell growth and osteoclast formation. / Hiruma, Yuko; Honjo, Tadashi; Jelinek, Diane F.; Windle, Jolene J.; Shin, Jaekyoon; Roodman, G. David; Kurihara, Noriyoshi.

In: Blood, Vol. 113, No. 20, 2009, p. 4894-4902.

Research output: Contribution to journalArticle

Hiruma, Yuko ; Honjo, Tadashi ; Jelinek, Diane F. ; Windle, Jolene J. ; Shin, Jaekyoon ; Roodman, G. David ; Kurihara, Noriyoshi. / Increased signaling through p62 in the marrow microenvironment increases myeloma cell growth and osteoclast formation. In: Blood. 2009 ; Vol. 113, No. 20. pp. 4894-4902.
@article{165bc1cee00c4284aef5874f67bc6e7c,
title = "Increased signaling through p62 in the marrow microenvironment increases myeloma cell growth and osteoclast formation",
abstract = "Adhesive interactions between multiple myeloma (MM) cells and marrow stromal cells activate multiple signaling pathways including nuclear factor κB (NF-κB), 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-κB 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-κB-dependent. Knocking-down p62 in patient-derived stromal cells significantly decreased protein kinase Cζ (PKCζ), 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-α (TNF-α), and receptor activator of NF-κB 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.",
author = "Yuko Hiruma and Tadashi Honjo and Jelinek, {Diane F.} and Windle, {Jolene J.} and Jaekyoon Shin and Roodman, {G. David} and Noriyoshi Kurihara",
year = "2009",
doi = "10.1182/blood-2008-08-173948",
language = "English (US)",
volume = "113",
pages = "4894--4902",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "20",

}

TY - JOUR

T1 - Increased signaling through p62 in the marrow microenvironment increases myeloma cell growth and osteoclast formation

AU - Hiruma, Yuko

AU - Honjo, Tadashi

AU - Jelinek, Diane F.

AU - Windle, Jolene J.

AU - Shin, Jaekyoon

AU - Roodman, G. David

AU - Kurihara, Noriyoshi

PY - 2009

Y1 - 2009

N2 - Adhesive interactions between multiple myeloma (MM) cells and marrow stromal cells activate multiple signaling pathways including nuclear factor κB (NF-κB), 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-κB 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-κB-dependent. Knocking-down p62 in patient-derived stromal cells significantly decreased protein kinase Cζ (PKCζ), 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-α (TNF-α), and receptor activator of NF-κB 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.

AB - Adhesive interactions between multiple myeloma (MM) cells and marrow stromal cells activate multiple signaling pathways including nuclear factor κB (NF-κB), 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-κB 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-κB-dependent. Knocking-down p62 in patient-derived stromal cells significantly decreased protein kinase Cζ (PKCζ), 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-α (TNF-α), and receptor activator of NF-κB 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.

UR - http://www.scopus.com/inward/record.url?scp=66549108847&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=66549108847&partnerID=8YFLogxK

U2 - 10.1182/blood-2008-08-173948

DO - 10.1182/blood-2008-08-173948

M3 - Article

C2 - 19282458

AN - SCOPUS:66549108847

VL - 113

SP - 4894

EP - 4902

JO - Blood

JF - Blood

SN - 0006-4971

IS - 20

ER -