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First published online 30 October 2007
doi: 10.1242/jcs.013946

Journal of Cell Science 120, 4009-4015 (2007)
Published by The Company of Biologists 2007
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Research Article

Midkine and LDL-receptor-related protein 1 contribute to the anchorage-independent cell growth of cancer cells

Sen Chen1, Guojun Bu2,3, Yoshifumi Takei1, Kazuma Sakamoto1, Shinya Ikematsu4, Takashi Muramatsu5 and Kenji Kadomatsu1,*

1 Department of Biochemistry, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
2 Department of Pediatrics, St Louis Children's Hospital, Washington University School of Medicine, St Louis, MO 63110, USA
3 Department of Cell Biology and Physiology, St Louis Children's Hospital, Washington University School of Medicine, St Louis, MO 63110, USA
4 Department of Bioresources Engineering, Okinawa National College of Technology, Okinawa 905-2192, Japan
5 Department of Health Science, Faculty of Psychological and Physical Sciences, Aichi Gakuin University, 12 Araike, Iwasaki-cho, Nisshin, Aichi 470-0195, Japan

* Author for correspondence (e-mail: kkadoma{at}med.nagoya-u.ac.jp)

Accepted 4 September 2007

The growth factor midkine (MK) is highly associated with cancer progression. Knockdown of MK expression strikingly suppresses tumor growth in nude mice. Thus, MK is a candidate target for cancer treatment. LDL-receptor-related protein 1 (LRP1) is a receptor for MK. We found that among the four ligand-binding domains of LRP1, the N-terminal half of the second domain (designated as MK-TRAP) had the strongest affinity to MK. MK-TRAP bound to MK, but not to HB-GAM/pleiotrophin, basic fibroblast growth factor or platelet-derived growth factor (PDGF)-BB. Exogenous MK-TRAP inhibited the binding between MK and LRP1. G401 cells that transiently or stably overexpress MK-TRAP showed decreased cell growth in monolayer culture and reduced colony formation in soft agar, which could be rescued by exogenous MK administration. MK-TRAP collected from conditioned medium also inhibited anchorage-independent growth of G401 cells and CMT-93 cells. Anti-MK antibody also inhibited the anchorage-independent growth. CMT-93 cells stably expressing MK-TRAP formed smaller tumors in a xenograft nude mouse model than control cells. Moreover, GST-RAP, a potent inhibitor of LRP1, inhibited the anchorage-independent growth of control G401 cells but not that of MK-TRAP stable transformants. Collectively, these data demonstrate a crucial role of MK-LRP1 signaling in anchorage-independent cell growth.

Key words: Midkine, LRP1, Dominant negative


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© The Company of Biologists Ltd 2007