Nature Medicine
- 12, 933 - 938 (2006)
Published online: 23 July 2006; | doi:10.1038/nm1444
Interaction of KAI1 on tumor cells with DARC on vascular endothelium leads to metastasis suppressionSucharita Bandyopadhyay1, Rui Zhan1, Asok Chaudhuri2, Misako Watabe1, Sudha K Pai1, Shigeru Hirota3, Sadahiro Hosobe3, Taisei Tsukada3, Kunio Miura3, Yukio Takano3, Ken Saito3, Mary E Pauza1, Sunao Hayashi1, Ying Wang1, Sonia Mohinta1, Tomoyuki Mashimo1, Megumi Iiizumi1, Eiji Furuta1 & Kounosuke Watabe11
Southern Illinois University School of Medicine, Department of Medical Microbiology, Immunology and Cell Biology, 801 N. Rutledge Street, PO Box 19626, Springfield, Illinois 62794-9626, USA. 2
Lindsley F. Kimball Research Institute of the New York Blood Center, 310 E. 67th St., New York, New York 10021, USA. 3
Akita Red Cross Hospital, 222-1 Saruta, Kitakamide, Akita City, Japan 010-1495.
Correspondence should be addressed to Kounosuke Watabe kwatabe@siumed.edu
CD82, also known as KAI1, was recently identified as a prostate cancer metastasis suppressor gene on human chromosome 11p1.2 (ref. 1). The product of CD82 is KAI1, a 40- to 75-kDa tetraspanin cell-surface protein also known as the leukocyte cell-surface marker CD82 (refs. 1,2). Downregulation of KAI1 has been found to be clinically associated with metastatic progression in a variety of cancers, whereas overexpression of CD82 specifically suppresses tumor metastasis in various animal models3. To define the mechanism of action of KAI1, we used a yeast two-hybrid screen and identified an endothelial cell-surface protein, DARC (also known as gp-Fy), as an interacting partner of KAI1. Our results indicate that the cancer cells expressing KAI1 attach to vascular endothelial cells through direct interaction between KAI1 and DARC, and that this interaction leads to inhibition of tumor cell proliferation and induction of senescence by modulating the expression of TBX2 and p21. Furthermore, the metastasis-suppression activity of KAI1 was significantly compromised in DARC knockout mice, whereas KAI1 completely abrogated pulmonary metastasis in wild-type and heterozygous littermates. These results provide direct evidence that DARC is essential for the function of CD82 as a suppressor of metastasis.
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