ZFIN ID: ZDB-PUB-170106-2
REP1 inhibits FOXO3-mediated apoptosis to promote cancer cell survival
Song, K.H., Woo, S.R., Chung, J.Y., Lee, H.J., Oh, S.J., Hong, S.O., Shim, J., Kim, Y.N., Rho, S.B., Hong, S.M., Cho, H., Hibi, M., Bae, D.J., Kim, S.Y., Kim, M.G., Kim, T.W., Bae, Y.K.
Date: 2017
Source: Cell Death & Disease   8: e2536 (Journal)
Registered Authors: Bae, Young Ki, Hibi, Masahiko
Keywords: none
MeSH Terms:
  • 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
PubMed: 28055019 Full text @ Cell Death Dis.
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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.
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