PMID- 17575106
OWN - NLM
STAT- MEDLINE
DCOM- 20070815
LR  - 20211203
IS  - 1535-7163 (Print)
IS  - 1535-7163 (Linking)
VI  - 6
IP  - 6
DP  - 2007 Jun
TI  - Wnt3/RhoA/ROCK signaling pathway is involved in adhesion-mediated drug resistance 
      of multiple myeloma in an autocrine mechanism.
PG  - 1774-84
AB  - Adhesion of myeloma cells to bone marrow stromal cells is now considered to play 
      a critical role in chemoresistance. However, little is known about the molecular 
      mechanism governing cell adhesion-mediated drug resistance (CAM-DR) of myeloma 
      cells. In this study, we focused our interests on the implication of the Wnt 
      signal in CAM-DR. We first screened the expression of Wnt family in myeloma cell 
      lines and found that Wnt3 was overexpressed in all the myeloma cells examined. 
      KMS-5 and ARH77, which highly expressed Wnt3 protein, tightly adhered to human 
      bone marrow stromal cells, and accumulation of beta-catenin and GTP-bounded RhoA 
      was observed in these myeloma cell lines. Conversely, RPMI8226 and MM1S, which 
      modestly expressed Wnt3 protein, rather weakly adhered to human bone marrow 
      stromal. We then examined the relevance of Wnt3 expression to adhesive property 
      to stromal cells and to CAM-DR of myeloma cells. KMS-5 and ARH-77 exhibited 
      apparent CAM-DR against doxorubicin. This CAM-DR was significantly reduced by 
      anti-integrin beta(1) antibody, anti-integrin alpha(6) antibody and a 
      Wnt-receptor competitor, secreted Frizzled-related protein-1, and Rho kinase 
      inhibitor Y27632, but not by the specific inhibitor of canonical signaling 
      (Dickkopf-1), indicating that Wnt-mediated CAM-DR that is dependent on integrin 
      alpha(6)/beta(1) (VLA-6)-mediated attachment to stromal cells is induced by the 
      Wnt/RhoA/Rho kinase pathway signal. This CAM-DR was also significantly reduced by 
      Wnt3 small interfering RNA transfer to KMS-5. These results indicate that Wnt3 
      contributes to VLA-6-mediated CAM-DR via the Wnt/RhoA/ROCK pathway of myeloma 
      cells in an autocrine manner. Thus, the Wnt3 signaling pathway could be a 
      promising molecular target to overcome CAM-DR of myeloma cells.
FAU - Kobune, Masayoshi
AU  - Kobune M
AD  - Fourth Department of Internal Medicine, Sapporo Medical University School of 
      Medicine, Sapporo, Japan.
FAU - Chiba, Hiroki
AU  - Chiba H
FAU - Kato, Junji
AU  - Kato J
FAU - Kato, Kazunori
AU  - Kato K
FAU - Nakamura, Kiminori
AU  - Nakamura K
FAU - Kawano, Yutaka
AU  - Kawano Y
FAU - Takada, Kohichi
AU  - Takada K
FAU - Takimoto, Rishu
AU  - Takimoto R
FAU - Takayama, Tetsuji
AU  - Takayama T
FAU - Hamada, Hirofumi
AU  - Hamada H
FAU - Niitsu, Yoshiro
AU  - Niitsu Y
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Mol Cancer Ther
JT  - Molecular cancer therapeutics
JID - 101132535
RN  - 0 (DNA Primers)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (WNT3 protein, human)
RN  - 0 (Wnt Proteins)
RN  - 0 (Wnt3 Protein)
RN  - 125361-02-6 (Vinculin)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (rho-Associated Kinases)
RN  - EC 3.6.5.2 (rhoA GTP-Binding Protein)
SB  - IM
MH  - Base Sequence
MH  - *Cell Adhesion
MH  - Cell Line, Tumor
MH  - DNA Primers
MH  - *Drug Resistance, Neoplasm
MH  - Humans
MH  - Intracellular Signaling Peptides and Proteins/*metabolism
MH  - Multiple Myeloma/metabolism/*pathology
MH  - Protein Serine-Threonine Kinases/*metabolism
MH  - *Signal Transduction
MH  - Vinculin/metabolism
MH  - Wnt Proteins/*metabolism
MH  - Wnt3 Protein
MH  - rho-Associated Kinases
MH  - rhoA GTP-Binding Protein/*metabolism
EDAT- 2007/06/19 09:00
MHDA- 2007/08/19 09:00
CRDT- 2007/06/19 09:00
PHST- 2007/06/19 09:00 [pubmed]
PHST- 2007/08/19 09:00 [medline]
PHST- 2007/06/19 09:00 [entrez]
AID - 6/6/1774 [pii]
AID - 10.1158/1535-7163.MCT-06-0684 [doi]
PST - ppublish
SO  - Mol Cancer Ther. 2007 Jun;6(6):1774-84. doi: 10.1158/1535-7163.MCT-06-0684.