title: RFPL4A increases the G1 population and decreases sensitivity to chemotherapy in human colorectal cancer cells.
abstract: Cell cycle-arrested cancer cells are resistant to conventional chemotherapy that acts on the mitotic phases of the cell cycle, although the molecular mechanisms involved in halting cell cycle progression remain unclear. Here, we demonstrated that RFPL4A, an uncharacterized ubiquitin ligase, induced G1 retention and thus conferred decreased sensitivity to chemotherapy in the human colorectal cancer cell line, HCT116. Long term time lapse observations in HCT116 cells bearing a "fluorescence ubiquitin-based cell cycle indicator" identified a characteristic population that is viable but remains in the G1 phase for an extended period of time (up to 56 h). Microarray analyses showed that expression of RFPL4A was significantly up-regulated in these G1-arrested cells, not only in HCT116 cells but also in other cancer cell lines, and overexpression of RFPL4A increased the G1 population and decreased sensitivity to chemotherapy. However, knockdown of RFPL4A expression caused the cells to resume mitosis and induced their susceptibility to anti-cancer drugs in vitro and in vivo. These results indicate that RFPL4A is a novel factor that increases the G1 population and decreases sensitivity to chemotherapy and thus may be a promising therapeutic target for refractory tumor conditions.
authors.affiliation: From the Departments of Immunology and Cell Biology, Gastroenterological Surgery, and.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Naito
authors.affiliation: Gastroenterological Surgery, and.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Yamamoto
authors.affiliation: From the Departments of Immunology and Cell Biology, Gastroenterological Surgery, and the WPI-Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Kagawa
authors.affiliation: From the Departments of Immunology and Cell Biology, the WPI-Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Naito
authors.affiliation: the DNA-chip Developmental Center for Infectious Diseases, Research Institute for Microbial Diseases, 3-1 Yamada-oka, Osaka University, Suita, Osaka 565-0871, Japan, and.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Okuzaki
authors.affiliation: From the Departments of Immunology and Cell Biology.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Otani
authors.affiliation: From the Departments of Immunology and Cell Biology.
authors.forename: Yoriko
authors.initials: Y
authors.lastname: Iwamoto
authors.affiliation: From the Departments of Immunology and Cell Biology, Gastroenterological Surgery, and the WPI-Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Sakae
authors.initials: S
authors.lastname: Maeda
authors.affiliation: From the Departments of Immunology and Cell Biology, the WPI-Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan, the Japan Science and Technology Agency (JST), CREST, 5 Sanban-cho, Chiyoda-ku, Tokyo 102-0075, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Kikuta
authors.affiliation: From the Departments of Immunology and Cell Biology, the WPI-Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan, the Japan Science and Technology Agency (JST), CREST, 5 Sanban-cho, Chiyoda-ku, Tokyo 102-0075, Japan.
authors.forename: Keizo
authors.initials: K
authors.lastname: Nishikawa
authors.affiliation: Gastroenterological Surgery, and.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Uemura
authors.affiliation: Gastroenterological Surgery, and.
authors.forename: Junichi
authors.initials: J
authors.lastname: Nishimura
authors.affiliation: Gastroenterological Surgery, and.
authors.forename: Taishi
authors.initials: T
authors.lastname: Hata
authors.affiliation: Gastroenterological Surgery, and.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Takemasa
authors.affiliation: Gastroenterological Surgery, and.
authors.forename: Tsunekazu
authors.initials: T
authors.lastname: Mizushima
authors.affiliation: Cancer Profiling Discovery, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Hideshi
authors.initials: H
authors.lastname: Ishii
authors.affiliation: Gastroenterological Surgery, and.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Doki
authors.affiliation: Gastroenterological Surgery, and mmori@gesrug.med.osaka-u.ac.jp.
authors.forename: Masaki
authors.initials: M
authors.lastname: Mori
authors.affiliation: From the Departments of Immunology and Cell Biology, the WPI-Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan, the Japan Science and Technology Agency (JST), CREST, 5 Sanban-cho, Chiyoda-ku, Tokyo 102-0075, Japan mishii@icb.med.osaka-u.ac.jp.
authors.forename: Masaru
authors.initials: M
authors.lastname: Ishii
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D016193:G1 Phase / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D046228:Microarray Analysis; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis*
chemical_list: D000970:Antineoplastic Agents; C000597689:RFPL4A protein, human; D044767:Ubiquitin-Protein Ligases
keywords: Anticancer Drug; Cell Cycle; Colon Cancer; E3 Ubiquitin Ligase; G1 Maintenance; Microarray; RFPL4A