title: Midkine and LDL-receptor-related protein 1 contribute to the anchorage-independent cell growth of cancer cells.
abstract: 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.
authors.affiliation: Department of Biochemistry, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Sen
authors.initials: S
authors.lastname: Chen
authors.forename: Guojun
authors.initials: G
authors.lastname: Bu
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Takei
authors.forename: Kazuma
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Shinya
authors.initials: S
authors.lastname: Ikematsu
authors.forename: Takashi
authors.initials: T
authors.lastname: Muramatsu
authors.forename: Kenji
authors.initials: K
authors.lastname: Kadomatsu
mesh_terms: D000818:Animals; D016466:CHO Cells; D019556:COS Cells; D002448:Cell Adhesion; D016923:Cell Death; D049109:Cell Proliferation; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D008024:Ligands; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D000078792:Midkine; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000473:pathology*; D009414:Nerve Growth Factors / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D014410:Tumor Stem Cell Assay
chemical_list: D008024:Ligands; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C066254:MDK protein, human; D009414:Nerve Growth Factors; D000078792:Midkine