RRC ID 49707
Author Song KH, Woo SR, Chung JY, Lee HJ, Oh SJ, Hong SO, Shim J, Kim YN, Rho SB, Hong SM, Cho H, Hibi M, Bae DJ, Kim SY, Kim MG, Kim TW, Bae YK.
Title REP1 inhibits FOXO3-mediated apoptosis to promote cancer cell survival.
Journal Cell Death Dis
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.
Volume 8(1)
Pages e2536
Published 2017-1-5
DOI 10.1038/cddis.2016.462
PII cddis2016462
PMID 28055019
PMC PMC5386371
MeSH Adaptor Proteins, Signal Transducing / biosynthesis Adaptor Proteins, Signal Transducing / genetics* Animals Apoptosis / genetics Carcinogenesis / genetics* Cell Line, Tumor Cell Survival / genetics Choroideremia / genetics Choroideremia / pathology Colonic Neoplasms / genetics* Colonic Neoplasms / pathology Disease Models, Animal Fluorouracil / administration & dosage Forkhead Box Protein O3 / biosynthesis Forkhead Box Protein O3 / genetics* Gene Expression Regulation, Neoplastic / drug effects Humans Mice Mutation Xenograft Model Antitumor Assays Zebrafish / genetics
IF 5.959
Zebrafish evanescence