Cargando…
REP1 inhibits FOXO3-mediated apoptosis to promote cancer cell survival
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 e...
Autores principales: | , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2017
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386371/ https://www.ncbi.nlm.nih.gov/pubmed/28055019 http://dx.doi.org/10.1038/cddis.2016.462 |
_version_ | 1782520757036777472 |
---|---|
author | Song, Kwon-Ho Woo, Seon Rang Chung, Joon-Yong Lee, Hyo-Jung Oh, Se Jin Hong, Soon-Oh Shim, Jaegal Kim, Yong Nyun Rho, Seung Bae Hong, Seung-Mo Cho, Hanbyoul Hibi, Masahiko Bae, Dong-Jun Kim, Sang-Yeob Kim, Min Gyu Kim, Tae Woo Bae, Young-Ki |
author_facet | Song, Kwon-Ho Woo, Seon Rang Chung, Joon-Yong Lee, Hyo-Jung Oh, Se Jin Hong, Soon-Oh Shim, Jaegal Kim, Yong Nyun Rho, Seung Bae Hong, Seung-Mo Cho, Hanbyoul Hibi, Masahiko Bae, Dong-Jun Kim, Sang-Yeob Kim, Min Gyu Kim, Tae Woo Bae, Young-Ki |
author_sort | Song, Kwon-Ho |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5386371 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-53863712017-04-26 REP1 inhibits FOXO3-mediated apoptosis to promote cancer cell survival Song, Kwon-Ho Woo, Seon Rang Chung, Joon-Yong Lee, Hyo-Jung Oh, Se Jin Hong, Soon-Oh Shim, Jaegal Kim, Yong Nyun Rho, Seung Bae Hong, Seung-Mo Cho, Hanbyoul Hibi, Masahiko Bae, Dong-Jun Kim, Sang-Yeob Kim, Min Gyu Kim, Tae Woo Bae, Young-Ki Cell Death Dis Original Article 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. Nature Publishing Group 2017-01 2017-01-05 /pmc/articles/PMC5386371/ /pubmed/28055019 http://dx.doi.org/10.1038/cddis.2016.462 Text en Copyright © 2017 The Author(s) http://creativecommons.org/licenses/by/4.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Original Article Song, Kwon-Ho Woo, Seon Rang Chung, Joon-Yong Lee, Hyo-Jung Oh, Se Jin Hong, Soon-Oh Shim, Jaegal Kim, Yong Nyun Rho, Seung Bae Hong, Seung-Mo Cho, Hanbyoul Hibi, Masahiko Bae, Dong-Jun Kim, Sang-Yeob Kim, Min Gyu Kim, Tae Woo Bae, Young-Ki REP1 inhibits FOXO3-mediated apoptosis to promote cancer cell survival |
title | REP1 inhibits FOXO3-mediated apoptosis to promote cancer cell survival |
title_full | REP1 inhibits FOXO3-mediated apoptosis to promote cancer cell survival |
title_fullStr | REP1 inhibits FOXO3-mediated apoptosis to promote cancer cell survival |
title_full_unstemmed | REP1 inhibits FOXO3-mediated apoptosis to promote cancer cell survival |
title_short | REP1 inhibits FOXO3-mediated apoptosis to promote cancer cell survival |
title_sort | rep1 inhibits foxo3-mediated apoptosis to promote cancer cell survival |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386371/ https://www.ncbi.nlm.nih.gov/pubmed/28055019 http://dx.doi.org/10.1038/cddis.2016.462 |
work_keys_str_mv | AT songkwonho rep1inhibitsfoxo3mediatedapoptosistopromotecancercellsurvival AT wooseonrang rep1inhibitsfoxo3mediatedapoptosistopromotecancercellsurvival AT chungjoonyong rep1inhibitsfoxo3mediatedapoptosistopromotecancercellsurvival AT leehyojung rep1inhibitsfoxo3mediatedapoptosistopromotecancercellsurvival AT ohsejin rep1inhibitsfoxo3mediatedapoptosistopromotecancercellsurvival AT hongsoonoh rep1inhibitsfoxo3mediatedapoptosistopromotecancercellsurvival AT shimjaegal rep1inhibitsfoxo3mediatedapoptosistopromotecancercellsurvival AT kimyongnyun rep1inhibitsfoxo3mediatedapoptosistopromotecancercellsurvival AT rhoseungbae rep1inhibitsfoxo3mediatedapoptosistopromotecancercellsurvival AT hongseungmo rep1inhibitsfoxo3mediatedapoptosistopromotecancercellsurvival AT chohanbyoul rep1inhibitsfoxo3mediatedapoptosistopromotecancercellsurvival AT hibimasahiko rep1inhibitsfoxo3mediatedapoptosistopromotecancercellsurvival AT baedongjun rep1inhibitsfoxo3mediatedapoptosistopromotecancercellsurvival AT kimsangyeob rep1inhibitsfoxo3mediatedapoptosistopromotecancercellsurvival AT kimmingyu rep1inhibitsfoxo3mediatedapoptosistopromotecancercellsurvival AT kimtaewoo rep1inhibitsfoxo3mediatedapoptosistopromotecancercellsurvival AT baeyoungki rep1inhibitsfoxo3mediatedapoptosistopromotecancercellsurvival |