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Targeting inhibition of extracellular signal-regulated kinase kinase pathway with AZD6244 (ARRY-142886) suppresses growth and angiogenesis of gastric cancer

AZD6244 (ARRY-142886), a highly selective MAPK-ERK kinase inhibitor, has shown excellent clinical efficacy in many tumors. However, the anti-tumor and anti-angiogenesis efficacy of AZD6244 on gastric cancer has not been well characterized. In this study, high p-ERK expression was associated with adv...

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Autores principales: Gao, Jin-Hang, Wang, Chun-Hui, Tong, Huan, Wen, Shi-Lei, Huang, Zhi-Yin, Tang, Cheng-Wei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4644956/
https://www.ncbi.nlm.nih.gov/pubmed/26567773
http://dx.doi.org/10.1038/srep16382
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author Gao, Jin-Hang
Wang, Chun-Hui
Tong, Huan
Wen, Shi-Lei
Huang, Zhi-Yin
Tang, Cheng-Wei
author_facet Gao, Jin-Hang
Wang, Chun-Hui
Tong, Huan
Wen, Shi-Lei
Huang, Zhi-Yin
Tang, Cheng-Wei
author_sort Gao, Jin-Hang
collection PubMed
description AZD6244 (ARRY-142886), a highly selective MAPK-ERK kinase inhibitor, has shown excellent clinical efficacy in many tumors. However, the anti-tumor and anti-angiogenesis efficacy of AZD6244 on gastric cancer has not been well characterized. In this study, high p-ERK expression was associated with advanced TNM stage, increased lymphovascular invasion and poor survival. For absence of NRAS, KRAS and BRAF mutation, SGC7901 and BGC823 gastric cancer cells were relative resistance to AZD6244 in vitro. And such resistance was not attributed to the insufficient inhibition of ERK phosphorylation. However, tumor growth was significantly suppressed in SGC7901 xenografts by blockage of angiogenesis. This result was further supported by suppression of tube formation and migration in HUVEC cells after treatment with AZD6244. Moreover, the anti-angiogenesis effect of AZD6244 may predominantly attribute to its modulation on VEGF through p-ERK − c-Fos − HIF-1α integrated signal pathways. In conclusions, High p-ERK expression was associated with advanced TNM stage, increased lymphovascular invasion and poor survival. Targeting inhibition of p-ERK by AZD6244 suppress gastric cancer xenografts by blockage of angiogenesis without systemic toxicity. The anti-angiogenesis effect afford by AZD6244 may attribute to its modulation on p-ERK − c-Fos − HIF-1α − VEGF integrated signal pathways.
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spelling pubmed-46449562015-11-20 Targeting inhibition of extracellular signal-regulated kinase kinase pathway with AZD6244 (ARRY-142886) suppresses growth and angiogenesis of gastric cancer Gao, Jin-Hang Wang, Chun-Hui Tong, Huan Wen, Shi-Lei Huang, Zhi-Yin Tang, Cheng-Wei Sci Rep Article AZD6244 (ARRY-142886), a highly selective MAPK-ERK kinase inhibitor, has shown excellent clinical efficacy in many tumors. However, the anti-tumor and anti-angiogenesis efficacy of AZD6244 on gastric cancer has not been well characterized. In this study, high p-ERK expression was associated with advanced TNM stage, increased lymphovascular invasion and poor survival. For absence of NRAS, KRAS and BRAF mutation, SGC7901 and BGC823 gastric cancer cells were relative resistance to AZD6244 in vitro. And such resistance was not attributed to the insufficient inhibition of ERK phosphorylation. However, tumor growth was significantly suppressed in SGC7901 xenografts by blockage of angiogenesis. This result was further supported by suppression of tube formation and migration in HUVEC cells after treatment with AZD6244. Moreover, the anti-angiogenesis effect of AZD6244 may predominantly attribute to its modulation on VEGF through p-ERK − c-Fos − HIF-1α integrated signal pathways. In conclusions, High p-ERK expression was associated with advanced TNM stage, increased lymphovascular invasion and poor survival. Targeting inhibition of p-ERK by AZD6244 suppress gastric cancer xenografts by blockage of angiogenesis without systemic toxicity. The anti-angiogenesis effect afford by AZD6244 may attribute to its modulation on p-ERK − c-Fos − HIF-1α − VEGF integrated signal pathways. Nature Publishing Group 2015-11-16 /pmc/articles/PMC4644956/ /pubmed/26567773 http://dx.doi.org/10.1038/srep16382 Text en Copyright © 2015, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ 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 Article
Gao, Jin-Hang
Wang, Chun-Hui
Tong, Huan
Wen, Shi-Lei
Huang, Zhi-Yin
Tang, Cheng-Wei
Targeting inhibition of extracellular signal-regulated kinase kinase pathway with AZD6244 (ARRY-142886) suppresses growth and angiogenesis of gastric cancer
title Targeting inhibition of extracellular signal-regulated kinase kinase pathway with AZD6244 (ARRY-142886) suppresses growth and angiogenesis of gastric cancer
title_full Targeting inhibition of extracellular signal-regulated kinase kinase pathway with AZD6244 (ARRY-142886) suppresses growth and angiogenesis of gastric cancer
title_fullStr Targeting inhibition of extracellular signal-regulated kinase kinase pathway with AZD6244 (ARRY-142886) suppresses growth and angiogenesis of gastric cancer
title_full_unstemmed Targeting inhibition of extracellular signal-regulated kinase kinase pathway with AZD6244 (ARRY-142886) suppresses growth and angiogenesis of gastric cancer
title_short Targeting inhibition of extracellular signal-regulated kinase kinase pathway with AZD6244 (ARRY-142886) suppresses growth and angiogenesis of gastric cancer
title_sort targeting inhibition of extracellular signal-regulated kinase kinase pathway with azd6244 (arry-142886) suppresses growth and angiogenesis of gastric cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4644956/
https://www.ncbi.nlm.nih.gov/pubmed/26567773
http://dx.doi.org/10.1038/srep16382
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