Cargando…

The RhoJ-BAD signaling network: An Achilles’ heel for BRAF mutant melanomas

Genes and pathways that allow cells to cope with oncogene-induced stress represent selective cancer therapeutic targets that remain largely undiscovered. In this study, we identify a RhoJ signaling pathway that is a selective therapeutic target for BRAF mutant cells. RhoJ deletion in BRAF mutant mel...

Descripción completa

Detalles Bibliográficos
Autores principales: Ruiz, Rolando, Jahid, Sohail, Harris, Melissa, Marzese, Diego M., Espitia, Francisco, Vasudeva, Priya, Chen, Chi-Fen, de Feraudy, Sebastien, Wu, Jie, Gillen, Daniel L., Krasieva, Tatiana B., Tromberg, Bruce J., Pavan, William J., Hoon, Dave S., Ganesan, Anand K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5549996/
https://www.ncbi.nlm.nih.gov/pubmed/28753606
http://dx.doi.org/10.1371/journal.pgen.1006913
_version_ 1783256061064511488
author Ruiz, Rolando
Jahid, Sohail
Harris, Melissa
Marzese, Diego M.
Espitia, Francisco
Vasudeva, Priya
Chen, Chi-Fen
de Feraudy, Sebastien
Wu, Jie
Gillen, Daniel L.
Krasieva, Tatiana B.
Tromberg, Bruce J.
Pavan, William J.
Hoon, Dave S.
Ganesan, Anand K.
author_facet Ruiz, Rolando
Jahid, Sohail
Harris, Melissa
Marzese, Diego M.
Espitia, Francisco
Vasudeva, Priya
Chen, Chi-Fen
de Feraudy, Sebastien
Wu, Jie
Gillen, Daniel L.
Krasieva, Tatiana B.
Tromberg, Bruce J.
Pavan, William J.
Hoon, Dave S.
Ganesan, Anand K.
author_sort Ruiz, Rolando
collection PubMed
description Genes and pathways that allow cells to cope with oncogene-induced stress represent selective cancer therapeutic targets that remain largely undiscovered. In this study, we identify a RhoJ signaling pathway that is a selective therapeutic target for BRAF mutant cells. RhoJ deletion in BRAF mutant melanocytes modulates the expression of the pro-apoptotic protein BAD as well as genes involved in cellular metabolism, impairing nevus formation, cellular transformation, and metastasis. Short-term treatment of nascent melanoma tumors with PAK inhibitors that block RhoJ signaling halts the growth of BRAF mutant melanoma tumors in vivo and induces apoptosis in melanoma cells in vitro via a BAD-dependent mechanism. As up to 50% of BRAF mutant human melanomas express high levels of RhoJ, these studies nominate the RhoJ-BAD signaling network as a therapeutic vulnerability for fledgling BRAF mutant human tumors.
format Online
Article
Text
id pubmed-5549996
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-55499962017-08-15 The RhoJ-BAD signaling network: An Achilles’ heel for BRAF mutant melanomas Ruiz, Rolando Jahid, Sohail Harris, Melissa Marzese, Diego M. Espitia, Francisco Vasudeva, Priya Chen, Chi-Fen de Feraudy, Sebastien Wu, Jie Gillen, Daniel L. Krasieva, Tatiana B. Tromberg, Bruce J. Pavan, William J. Hoon, Dave S. Ganesan, Anand K. PLoS Genet Research Article Genes and pathways that allow cells to cope with oncogene-induced stress represent selective cancer therapeutic targets that remain largely undiscovered. In this study, we identify a RhoJ signaling pathway that is a selective therapeutic target for BRAF mutant cells. RhoJ deletion in BRAF mutant melanocytes modulates the expression of the pro-apoptotic protein BAD as well as genes involved in cellular metabolism, impairing nevus formation, cellular transformation, and metastasis. Short-term treatment of nascent melanoma tumors with PAK inhibitors that block RhoJ signaling halts the growth of BRAF mutant melanoma tumors in vivo and induces apoptosis in melanoma cells in vitro via a BAD-dependent mechanism. As up to 50% of BRAF mutant human melanomas express high levels of RhoJ, these studies nominate the RhoJ-BAD signaling network as a therapeutic vulnerability for fledgling BRAF mutant human tumors. Public Library of Science 2017-07-28 /pmc/articles/PMC5549996/ /pubmed/28753606 http://dx.doi.org/10.1371/journal.pgen.1006913 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 (https://creativecommons.org/publicdomain/zero/1.0/) public domain dedication.
spellingShingle Research Article
Ruiz, Rolando
Jahid, Sohail
Harris, Melissa
Marzese, Diego M.
Espitia, Francisco
Vasudeva, Priya
Chen, Chi-Fen
de Feraudy, Sebastien
Wu, Jie
Gillen, Daniel L.
Krasieva, Tatiana B.
Tromberg, Bruce J.
Pavan, William J.
Hoon, Dave S.
Ganesan, Anand K.
The RhoJ-BAD signaling network: An Achilles’ heel for BRAF mutant melanomas
title The RhoJ-BAD signaling network: An Achilles’ heel for BRAF mutant melanomas
title_full The RhoJ-BAD signaling network: An Achilles’ heel for BRAF mutant melanomas
title_fullStr The RhoJ-BAD signaling network: An Achilles’ heel for BRAF mutant melanomas
title_full_unstemmed The RhoJ-BAD signaling network: An Achilles’ heel for BRAF mutant melanomas
title_short The RhoJ-BAD signaling network: An Achilles’ heel for BRAF mutant melanomas
title_sort rhoj-bad signaling network: an achilles’ heel for braf mutant melanomas
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5549996/
https://www.ncbi.nlm.nih.gov/pubmed/28753606
http://dx.doi.org/10.1371/journal.pgen.1006913
work_keys_str_mv AT ruizrolando therhojbadsignalingnetworkanachillesheelforbrafmutantmelanomas
AT jahidsohail therhojbadsignalingnetworkanachillesheelforbrafmutantmelanomas
AT harrismelissa therhojbadsignalingnetworkanachillesheelforbrafmutantmelanomas
AT marzesediegom therhojbadsignalingnetworkanachillesheelforbrafmutantmelanomas
AT espitiafrancisco therhojbadsignalingnetworkanachillesheelforbrafmutantmelanomas
AT vasudevapriya therhojbadsignalingnetworkanachillesheelforbrafmutantmelanomas
AT chenchifen therhojbadsignalingnetworkanachillesheelforbrafmutantmelanomas
AT deferaudysebastien therhojbadsignalingnetworkanachillesheelforbrafmutantmelanomas
AT wujie therhojbadsignalingnetworkanachillesheelforbrafmutantmelanomas
AT gillendaniell therhojbadsignalingnetworkanachillesheelforbrafmutantmelanomas
AT krasievatatianab therhojbadsignalingnetworkanachillesheelforbrafmutantmelanomas
AT trombergbrucej therhojbadsignalingnetworkanachillesheelforbrafmutantmelanomas
AT pavanwilliamj therhojbadsignalingnetworkanachillesheelforbrafmutantmelanomas
AT hoondaves therhojbadsignalingnetworkanachillesheelforbrafmutantmelanomas
AT ganesananandk therhojbadsignalingnetworkanachillesheelforbrafmutantmelanomas
AT ruizrolando rhojbadsignalingnetworkanachillesheelforbrafmutantmelanomas
AT jahidsohail rhojbadsignalingnetworkanachillesheelforbrafmutantmelanomas
AT harrismelissa rhojbadsignalingnetworkanachillesheelforbrafmutantmelanomas
AT marzesediegom rhojbadsignalingnetworkanachillesheelforbrafmutantmelanomas
AT espitiafrancisco rhojbadsignalingnetworkanachillesheelforbrafmutantmelanomas
AT vasudevapriya rhojbadsignalingnetworkanachillesheelforbrafmutantmelanomas
AT chenchifen rhojbadsignalingnetworkanachillesheelforbrafmutantmelanomas
AT deferaudysebastien rhojbadsignalingnetworkanachillesheelforbrafmutantmelanomas
AT wujie rhojbadsignalingnetworkanachillesheelforbrafmutantmelanomas
AT gillendaniell rhojbadsignalingnetworkanachillesheelforbrafmutantmelanomas
AT krasievatatianab rhojbadsignalingnetworkanachillesheelforbrafmutantmelanomas
AT trombergbrucej rhojbadsignalingnetworkanachillesheelforbrafmutantmelanomas
AT pavanwilliamj rhojbadsignalingnetworkanachillesheelforbrafmutantmelanomas
AT hoondaves rhojbadsignalingnetworkanachillesheelforbrafmutantmelanomas
AT ganesananandk rhojbadsignalingnetworkanachillesheelforbrafmutantmelanomas