title: Novel small molecule inhibiting CDCP1-PKCδ pathway reduces tumor metastasis and proliferation.
abstract: CUB domain-containing protein-1 (CDCP1) is a trans-membrane protein predominantly expressed in various cancer cells and involved in tumor progression. CDCP1 is phosphorylated at tyrosine residues in the intracellular domain by Src family kinases and recruits PKCδ to the plasma membrane through tyrosine phosphorylation-dependent association with the C2 domain of PKCδ, which in turn induces a survival signal in an anchorage-independent condition. In this study, we used our cell-free screening system to identify a small compound, glycoconjugated palladium complex (Pd-Oqn), which significantly inhibited the interaction between the C2 domain of PKCδ and phosphorylated CDCP1. Immunoprecipitation assays demonstrated that Pd-Oqn hindered the intercellular interaction of phosphorylated CDCP1 with PKCδ and also suppressed the phosphorylation of PKCδ but not that of ERK or AKT. In addition, Pd-Oqn inhibited the colony formation of gastric adenocarcinoma 44As3 cells in soft agar as well as their invasion. In mouse models, Pd-Oqn markedly reduced the peritoneal dissemination of gastric adenocarcinoma cells and the tumor growth of pancreatic cancer orthotopic xenografts. These results suggest that the novel compound Pd-Oqn reduces tumor metastasis and growth by inhibiting the association between CDCP1 and PKCδ, thus potentially representing a promising candidate among therapeutic reagents targeting protein-protein interaction.
authors.affiliation: Division of Refractory and Advanced Cancer, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Katsuhiko
authors.identifier: http://orcid.org/0000-0003-2970-1049
authors.initials: K
authors.lastname: Nakashima
authors.affiliation: Department of Applied Chemistry, National Defense Academy, Yokosuka, Japan.
authors.forename: Takamasa
authors.initials: T
authors.lastname: Uekita
authors.affiliation: Graduate School of Materials Science, Nara Institute of Science and Technology, Nara, Japan.
authors.forename: Shigenobu
authors.initials: S
authors.lastname: Yano
authors.affiliation: Graduate School of Materials Science, Nara Institute of Science and Technology, Nara, Japan.
authors.forename: Jun-Ichi
authors.initials: JI
authors.lastname: Kikuchi
authors.affiliation: Division of Refractory and Advanced Cancer, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Ruri
authors.initials: R
authors.lastname: Nakanishi
authors.affiliation: Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, Osaka, Japan.
authors.forename: Nozomi
authors.initials: N
authors.lastname: Sakamoto
authors.affiliation: Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, Osaka, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Fukumoto
authors.affiliation: Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, Osaka, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Nomoto
authors.affiliation: Department of Chemistry, Graduate School of Natural Science, Kanazawa University, Kanazawa, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kawamoto
authors.affiliation: Department of Chemistry, Okayama University of Science, Okayama, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Shibahara
authors.affiliation: Division of Refractory and Advanced Cancer, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Yamaguchi
authors.affiliation: Division of Refractory and Advanced Cancer, National Cancer Center Research Institute, Tokyo, Japan.|Division of Biochemistry, Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Sakai
mesh_terms: D000072283:A549 Cells; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000188:drug therapy*; D009363:Neoplasm Proteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051745:Protein Kinase C-delta / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000494:pharmacology*
chemical_list: D009363:Neoplasm Proteins; D054852:Small Molecule Libraries; D051057:Proto-Oncogene Proteins c-akt; D051745:Protein Kinase C-delta
keywords: CDCP1; PKCδ; Src; chemical screening; metastasis