title: REP1 inhibits FOXO3-mediated apoptosis to promote cancer cell survival.
abstract: Rab escort protein 1 (REP1) is a component of Rab geranyl-geranyl transferase 2 complex. Mutations in REP1 cause a disease called choroideremia (CHM), which is an X-linked eye disease. Although it is postulated that REP1 has functions in cell survival or death of various tissues in addition to the eye, how REP1 functions in normal and cancer cells remains to be elucidated. Here, we demonstrated that REP1 is required for the survival of intestinal cells in addition to eyes or a variety of cells in zebrafish, and also has important roles in tumorigenesis. Notably, REP1 is highly expressed in colon cancer tissues and cell lines, and silencing of REP1 sensitizes colon cancer cells to serum starvation- and 5-FU-induced apoptosis. In an effort to elucidate the molecular mechanisms underlying REP1-mediated cell survival under those stress conditions, we identified FOXO3 as a binding partner of REP1 using a yeast two-hybrid (Y2H) assay system, and we demonstrated that REP1 blocked the nuclear trans-localization of FOXO3 through physically interacting with FOXO3, thereby suppressing FOXO3-mediated apoptosis. Importantly, the inhibition of REP1 combined with 5-FU treatment could lead to significant retarded tumor growth in a xenograft tumor model of human cancer cells. Thus, our results suggest that REP1 could be a new therapeutic target in combination treatment for colon cancer patients.
authors.affiliation: Laboratory of Tumor Immunology, Department of Biomedical Sciences, Graduate School of Medicine, Korea University, Seoul, Republic of Korea.|Department of Biochemistry, Korea University College of Medicine, Seoul, Republic of Korea.|Department of Biomedical Sciences, College of Medicine, Korea University, Seoul, Republic of Korea.
authors.forename: Kwon-Ho
authors.initials: KH
authors.lastname: Song
authors.affiliation: Laboratory of Tumor Immunology, Department of Biomedical Sciences, Graduate School of Medicine, Korea University, Seoul, Republic of Korea.|Department of Biochemistry, Korea University College of Medicine, Seoul, Republic of Korea.|Translational Research Institute for Incurable Diseases, Korea University College of Medicine, Seoul, Republic of Korea.
authors.forename: Seon Rang
authors.initials: SR
authors.lastname: Woo
authors.affiliation: Experimental Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Joon-Yong
authors.initials: JY
authors.lastname: Chung
authors.affiliation: Laboratory of Tumor Immunology, Department of Biomedical Sciences, Graduate School of Medicine, Korea University, Seoul, Republic of Korea.|Department of Biochemistry, Korea University College of Medicine, Seoul, Republic of Korea.|Department of Biomedical Sciences, College of Medicine, Korea University, Seoul, Republic of Korea.
authors.forename: Hyo-Jung
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Laboratory of Tumor Immunology, Department of Biomedical Sciences, Graduate School of Medicine, Korea University, Seoul, Republic of Korea.|Department of Biochemistry, Korea University College of Medicine, Seoul, Republic of Korea.|Department of Biomedical Sciences, College of Medicine, Korea University, Seoul, Republic of Korea.
authors.forename: Se Jin
authors.initials: SJ
authors.lastname: Oh
authors.affiliation: Laboratory of Tumor Immunology, Department of Biomedical Sciences, Graduate School of Medicine, Korea University, Seoul, Republic of Korea.|Department of Biochemistry, Korea University College of Medicine, Seoul, Republic of Korea.|Department of Biomedical Sciences, College of Medicine, Korea University, Seoul, Republic of Korea.
authors.forename: Soon-Oh
authors.initials: SO
authors.lastname: Hong
authors.affiliation: Comparative Biomedicine Research Branch, Research Institute, National Cancer Center, Goyang, Republic of Korea.
authors.forename: Jaegal
authors.initials: J
authors.lastname: Shim
authors.affiliation: Comparative Biomedicine Research Branch, Research Institute, National Cancer Center, Goyang, Republic of Korea.
authors.forename: Yong Nyun
authors.initials: YN
authors.lastname: Kim
authors.affiliation: Gynecologic Cancer Branch, Research Institute, National Cancer Center, Goyang, Republic of Korea.
authors.forename: Seung Bae
authors.initials: SB
authors.lastname: Rho
authors.affiliation: Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea.
authors.forename: Seung-Mo
authors.initials: SM
authors.lastname: Hong
authors.affiliation: Experimental Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.|Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Hanbyoul
authors.initials: H
authors.lastname: Cho
authors.affiliation: Bioscience and Biotechnology Center, Nagoya University, Nagoya, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Hibi
authors.affiliation: ASAN Institute for Life Sciences, ASAN Medical Center, Seoul, Republic of Korea.
authors.forename: Dong-Jun
authors.initials: DJ
authors.lastname: Bae
authors.affiliation: ASAN Institute for Life Sciences, ASAN Medical Center, Seoul, Republic of Korea.|Department of Convergence Medicine, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Sang-Yeob
authors.initials: SY
authors.lastname: Kim
authors.affiliation: School of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Min Gyu
authors.initials: MG
authors.lastname: Kim
authors.affiliation: Laboratory of Tumor Immunology, Department of Biomedical Sciences, Graduate School of Medicine, Korea University, Seoul, Republic of Korea.|Department of Biochemistry, Korea University College of Medicine, Seoul, Republic of Korea.|Department of Biomedical Sciences, College of Medicine, Korea University, Seoul, Republic of Korea.|Translational Research Institute for Incurable Diseases, Korea University College of Medicine, Seoul, Republic of Korea.
authors.forename: Tae Woo
authors.initials: TW
authors.lastname: Kim
authors.affiliation: Comparative Biomedicine Research Branch, Research Institute, National Cancer Center, Goyang, Republic of Korea.
authors.forename: Young-Ki
authors.identifier: 0000-0001-7964-3540
authors.initials: YK
authors.lastname: Bae
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D063646:Carcinogenesis / Q000235:genetics*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D015794:Choroideremia / Q000235:genetics / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D005472:Fluorouracil / Q000008:administration & dosage; D000071316:Forkhead Box Protein O3 / Q000096:biosynthesis / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D009154:Mutation; D023041:Xenograft Model Antitumor Assays; D015027:Zebrafish / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C081787:CHM protein, human; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D005472:Fluorouracil