title: Involvement of the SKP2-p27(KIP1) pathway in suppression of cancer cell proliferation by RECK.
abstract: The membrane-anchored matrix metalloproteinase-regulator RECK is often downregulated in cancers; in some cases, a significant correlation between the level of residual RECK in resected tumors and patient survival has been noted. Furthermore, restoration of RECK expression in certain cancer-derived cell lines results in reduced tumorigenicity. Here we report that acute RECK expression in colon carcinoma cells results in cell cycle-arrest accompanied by downregulation of a ubiquitin ligase component, S-phase kinase-associated protein 2 (SKP2), and upregulation of its substrate, p27(KIP1). Our data indicate that RECK-induced growth suppression is at least partially dependent on p27, and that RECK and type I collagen share similar effects on the SKP2-p27 pathway. Importantly, in patients with lung, colorectal and bladder cancers, the RECK/SKP2 ratio is high in normal tissues and lower in the cancer tissues. These findings reveal a novel molecular pathway linking cell-cycle progression to RECK downregulation, extracellular matrix degradation and SKP2 upregulation, and suggest that treatment regimens that induce RECK expression could be promising cancer therapies.
authors.affiliation: Department of Molecular Oncology and Global COE Program, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Yoshida
authors.forename: K
authors.initials: K
authors.lastname: Ninomiya
authors.forename: H
authors.initials: H
authors.lastname: Hamada
authors.forename: M
authors.initials: M
authors.lastname: Noda
mesh_terms: D000818:Animals; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D015536:Down-Regulation; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering; D044786:S-Phase Kinase-Associated Proteins / Q000096:biosynthesis*; D015854:Up-Regulation
chemical_list: D058851:GPI-Linked Proteins; C115460:RECK protein, human; D034741:RNA, Small Interfering; D044786:S-Phase Kinase-Associated Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27