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Research Articles: Therapeutics, Targets, and Development

Wnt3/RhoA/ROCK signaling pathway is involved in adhesion-mediated drug resistance of multiple myeloma in an autocrine mechanism

¹ Fourth Department of Internal Medicine and ² Department of Molecular Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan

Requests for reprints: Yoshiro Niitsu, Fourth Department of Internal Medicine, Sapporo Medical University, Chuo-ku S1, W17, Sapporo, 060-8556, Japan. Phone: 81-11-611-2111, ext. 3254; Fax: 81-11-612-7987. E-mail: niitsu{at}sapmed.ac.jp

Abstract

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 ß-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 ß₁ antibody, anti-integrin 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 ₆/ß₁ (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. [Mol Cancer Ther 2007;6(6):1774–82]

Grant support: Ministry of Education, Culture, Sports, Science and Technology of Japan (H. Hamada) and Ministry of Health, Labour and Welfare of Japan (M. Kobune).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: M. Kobune and H. Chiba contributed equally to this work.

³ Supplementary material for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 11/ 7/06; revised 3/23/07; accepted 5/ 1/07.