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Oncogenic K-Ras Activates p38 to Maintain Colorectal Cancer Cell Proliferation during MEK Inhibition

Background: Colon carcinomas frequently contain activating mutations in the K-ras proto-oncogene. K-ras itself is a poor drug target and drug development efforts have mostly focused on components of the classical Ras-activated MEK/ERK pathway. Here we have studied whether endogenous oncogenic K-ras...

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Autores principales: van Houdt, Winan J., de Bruijn, Menno T., Emmink, Benjamin L., Raats, Danielle, Hoogwater, Frederik J. H., Rinkes, Inne H. M. Borel, Kranenburg, Onno
Formato: Online Artículo Texto
Lenguaje:English
Publicado: IOS Press 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4619241/
https://www.ncbi.nlm.nih.gov/pubmed/20413844
http://dx.doi.org/10.3233/CLO-2010-0521
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author van Houdt, Winan J.
de Bruijn, Menno T.
Emmink, Benjamin L.
Raats, Danielle
Hoogwater, Frederik J. H.
Rinkes, Inne H. M. Borel
Kranenburg, Onno
author_facet van Houdt, Winan J.
de Bruijn, Menno T.
Emmink, Benjamin L.
Raats, Danielle
Hoogwater, Frederik J. H.
Rinkes, Inne H. M. Borel
Kranenburg, Onno
author_sort van Houdt, Winan J.
collection PubMed
description Background: Colon carcinomas frequently contain activating mutations in the K-ras proto-oncogene. K-ras itself is a poor drug target and drug development efforts have mostly focused on components of the classical Ras-activated MEK/ERK pathway. Here we have studied whether endogenous oncogenic K-ras affects the dependency of colorectal tumor cells on MEK/ERK signaling. Methods: K-ras mutant colorectal tumor cell lines C26, HCT116 and L169 were used. K-ras or components of the MEK/ERK and p38 pathway were suppressed by RNA interference (RNAi). MEK was inhibited by U0126. p38 was inhibited by SB203850. Results: MEK inhibition, or suppression of MEK1/2 or ERK1/2 by RNA interference, reduced the proliferation rate of all colorectal cancer cell lines. However, cell proliferation returned to normal after two weeks of chronic inhibition, despite the continued suppression of MEK or ERK. In contrast, K-ras-suppressed tumor cells entered an irreversible senescent-like state following ERK pathway inhibition. MEK inhibition or ERK1/2 suppression caused activation of p38α in a K-ras-dependent manner. Inhibition or suppression of p38α prevented the recovery of K-ras mutant tumor cells during prolonged MEK inhibition. Conclusions: Oncogenic K-ras activates p38α to maintain cell proliferation during MEK inhibition. MEK-targeting therapeutics can create an acquired tumor cell dependency on p38α.
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spelling pubmed-46192412016-01-12 Oncogenic K-Ras Activates p38 to Maintain Colorectal Cancer Cell Proliferation during MEK Inhibition van Houdt, Winan J. de Bruijn, Menno T. Emmink, Benjamin L. Raats, Danielle Hoogwater, Frederik J. H. Rinkes, Inne H. M. Borel Kranenburg, Onno Cell Oncol Other Background: Colon carcinomas frequently contain activating mutations in the K-ras proto-oncogene. K-ras itself is a poor drug target and drug development efforts have mostly focused on components of the classical Ras-activated MEK/ERK pathway. Here we have studied whether endogenous oncogenic K-ras affects the dependency of colorectal tumor cells on MEK/ERK signaling. Methods: K-ras mutant colorectal tumor cell lines C26, HCT116 and L169 were used. K-ras or components of the MEK/ERK and p38 pathway were suppressed by RNA interference (RNAi). MEK was inhibited by U0126. p38 was inhibited by SB203850. Results: MEK inhibition, or suppression of MEK1/2 or ERK1/2 by RNA interference, reduced the proliferation rate of all colorectal cancer cell lines. However, cell proliferation returned to normal after two weeks of chronic inhibition, despite the continued suppression of MEK or ERK. In contrast, K-ras-suppressed tumor cells entered an irreversible senescent-like state following ERK pathway inhibition. MEK inhibition or ERK1/2 suppression caused activation of p38α in a K-ras-dependent manner. Inhibition or suppression of p38α prevented the recovery of K-ras mutant tumor cells during prolonged MEK inhibition. Conclusions: Oncogenic K-ras activates p38α to maintain cell proliferation during MEK inhibition. MEK-targeting therapeutics can create an acquired tumor cell dependency on p38α. IOS Press 2010 2010-04-22 /pmc/articles/PMC4619241/ /pubmed/20413844 http://dx.doi.org/10.3233/CLO-2010-0521 Text en Copyright © 2010 Hindawi Publishing Corporation and the authors.
spellingShingle Other
van Houdt, Winan J.
de Bruijn, Menno T.
Emmink, Benjamin L.
Raats, Danielle
Hoogwater, Frederik J. H.
Rinkes, Inne H. M. Borel
Kranenburg, Onno
Oncogenic K-Ras Activates p38 to Maintain Colorectal Cancer Cell Proliferation during MEK Inhibition
title Oncogenic K-Ras Activates p38 to Maintain Colorectal Cancer Cell Proliferation during MEK Inhibition
title_full Oncogenic K-Ras Activates p38 to Maintain Colorectal Cancer Cell Proliferation during MEK Inhibition
title_fullStr Oncogenic K-Ras Activates p38 to Maintain Colorectal Cancer Cell Proliferation during MEK Inhibition
title_full_unstemmed Oncogenic K-Ras Activates p38 to Maintain Colorectal Cancer Cell Proliferation during MEK Inhibition
title_short Oncogenic K-Ras Activates p38 to Maintain Colorectal Cancer Cell Proliferation during MEK Inhibition
title_sort oncogenic k-ras activates p38 to maintain colorectal cancer cell proliferation during mek inhibition
topic Other
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4619241/
https://www.ncbi.nlm.nih.gov/pubmed/20413844
http://dx.doi.org/10.3233/CLO-2010-0521
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