title: Wnt5a promotes cancer cell invasion and proliferation by receptor-mediated endocytosis-dependent and -independent mechanisms, respectively.
abstract: Wnt5a activates the Wnt/β-catenin-independent pathway and its overexpression is associated with tumor aggressiveness enhancing invasive activity. For this action, Wnt5a-induced receptor endocytosis with clathrin is required. Wnt5a expression was previously believed to be associated with cancer cell motility but not proliferation. Recently, it was reported that Wnt5a is also implicated in cancer cell proliferation, but the mechanism was not clear. In this study, we generated a neutralizing anti-Wnt5a monoclonal antibody (mAb5A16) to investigate the mechanism by which Wnt5a regulates cancer cell proliferation. Wnt5a stimulated both invasion and proliferation of certain types of cancer cells, including HeLaS3 cervical cancer cells and A549 lung cancer cells although Wnt5a promoted invasion but not proliferation in other cancer cells such as KKLS gastric cancer cells. mAb5A16 did not affect the binding of Wnt5a to its receptor, but it suppressed Wnt5a-induced receptor-mediated endocytosis. mAb5A16 inhibited invasion but not proliferation of HeLaS3 and A549 cells. Wnt5a activated Src family kinases (SFKs) and Wnt5a-dependent cancer cell proliferation was dependent on SFKs, yet blockade of receptor-mediated endocytosis did not affect cancer cell proliferation and SFK activity. These results suggest that Wnt5a promotes invasion and proliferation of certain types of cancer cells through receptor-mediated endocytosis-dependent and -independent mechanisms, respectively.
authors.affiliation: Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita 565-0871, Japan.
authors.forename: Kensaku
authors.initials: K
authors.lastname: Shojima
authors.affiliation: Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita 565-0871, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Sato
authors.affiliation: Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita 565-0871, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Hanaki
authors.affiliation: Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita 565-0871, Japan.
authors.forename: Ikuko
authors.initials: I
authors.lastname: Tsujimoto
authors.affiliation: Diagnostics Division, Discovery Research Laboratory for Innovative Frontier Medicines, Shionogi &Co., Ltd. 1-1, Futaba-cho 3-chome, Toyonaka, 561-0825, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Department of Informatics &Structure-based Drug Discovery, Discovery Research Laboratory for Innovative Frontier Medicines, Shionogi &Co., Ltd. 1-1, Futaba-cho 3-chome, Toyonaka, 561-0825, Japan.
authors.forename: Kazunari
authors.initials: K
authors.lastname: Hattori
authors.affiliation: Department of Oncology &Immunology, Discovery Research Laboratory for Innovative Frontier Medicines, Shionogi &Co., Ltd. 1-1, Futaba-cho 3-chome, Toyonaka, 561-0825, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Department of Oncology &Immunology, Discovery Research Laboratory for Innovative Frontier Medicines, Shionogi &Co., Ltd. 1-1, Futaba-cho 3-chome, Toyonaka, 561-0825, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Dohi
authors.affiliation: Department of Oncology &Immunology, Discovery Research Laboratory for Innovative Frontier Medicines, Shionogi &Co., Ltd. 1-1, Futaba-cho 3-chome, Toyonaka, 561-0825, Japan.
authors.forename: Michinari
authors.initials: M
authors.lastname: Hirata
authors.affiliation: Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita 565-0871, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Yamamoto
authors.affiliation: Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita 565-0871, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Kikuchi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004705:Endocytosis / Q000187:drug effects; D000939:Epitopes / Q000276:immunology; D006367:HeLa Cells; D006801:Humans; D008113:Liver Neoplasms / Q000517:prevention & control / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D019151:Peptide Library; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D060490:Receptors, Wnt / Q000276:immunology / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000473:pathology; D014183:Transplantation, Heterologous; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000187:drug effects; D000071818:Wnt-5a Protein; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000939:Epitopes; D019151:Peptide Library; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D060490:Receptors, Wnt; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D019061:src-Family Kinases