Cargando…
Suppression of esophageal tumor growth and chemoresistance by directly targeting the PI3K/AKT pathway
Esophageal cancer is the sixth most common cause of cancer-related deaths worldwide. Novel therapeutic intervention is urgently needed for this deadly disease. The functional role of PI3K/AKT pathway in esophageal cancer is little known. In this study, our results from 49 pairs of human esophageal t...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2014
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4294385/ https://www.ncbi.nlm.nih.gov/pubmed/25344912 |
_version_ | 1782352721521672192 |
---|---|
author | Li, Bin Li, Jin Xu, Wen Wen Guan, Xin Yuan Qin, Yan Ru Zhang, Li Yi Law, Simon Tsao, Sai Wah Cheung, Annie L.M. |
author_facet | Li, Bin Li, Jin Xu, Wen Wen Guan, Xin Yuan Qin, Yan Ru Zhang, Li Yi Law, Simon Tsao, Sai Wah Cheung, Annie L.M. |
author_sort | Li, Bin |
collection | PubMed |
description | Esophageal cancer is the sixth most common cause of cancer-related deaths worldwide. Novel therapeutic intervention is urgently needed for this deadly disease. The functional role of PI3K/AKT pathway in esophageal cancer is little known. In this study, our results from 49 pairs of human esophageal tumor and normal specimens demonstrated that AKT was constitutively active in the majority (75.5%) of esophageal tumors compared with corresponding normal tissues. Inhibition of the PI3K/AKT pathway with specific inhibitors, wortmannin and LY294002, significantly reduced Bcl-xL expression, induced caspase-3-dependent apoptosis, and repressed cell proliferation and tumor growth in vitro and in vivo without obvious toxic effects. Moreover, significantly higher expression level of p-AKT was observed in fluorouracil (5-FU)-resistant esophageal cancer cells. Inactivation of PI3K/AKT pathway markedly increased the sensitivity and even reversed acquired resistance of esophageal cancer cells to chemotherapeutic drugs in vitro. More importantly, the resistance of tumor xenografts derived from esophageal cancer cells with acquired 5-FU resistance to chemotherapeutic drugs was significantly abrogated by wortmannin treatment in animals. In summary, our data support PI3K/AKT as a valid therapeutic target and strongly suggest that PI3K/AKT inhibitors used in conjunction with conventional chemotherapy may be a potentially useful therapeutic strategy in treating esophageal cancer patients. |
format | Online Article Text |
id | pubmed-4294385 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-42943852015-01-21 Suppression of esophageal tumor growth and chemoresistance by directly targeting the PI3K/AKT pathway Li, Bin Li, Jin Xu, Wen Wen Guan, Xin Yuan Qin, Yan Ru Zhang, Li Yi Law, Simon Tsao, Sai Wah Cheung, Annie L.M. Oncotarget Research Paper Esophageal cancer is the sixth most common cause of cancer-related deaths worldwide. Novel therapeutic intervention is urgently needed for this deadly disease. The functional role of PI3K/AKT pathway in esophageal cancer is little known. In this study, our results from 49 pairs of human esophageal tumor and normal specimens demonstrated that AKT was constitutively active in the majority (75.5%) of esophageal tumors compared with corresponding normal tissues. Inhibition of the PI3K/AKT pathway with specific inhibitors, wortmannin and LY294002, significantly reduced Bcl-xL expression, induced caspase-3-dependent apoptosis, and repressed cell proliferation and tumor growth in vitro and in vivo without obvious toxic effects. Moreover, significantly higher expression level of p-AKT was observed in fluorouracil (5-FU)-resistant esophageal cancer cells. Inactivation of PI3K/AKT pathway markedly increased the sensitivity and even reversed acquired resistance of esophageal cancer cells to chemotherapeutic drugs in vitro. More importantly, the resistance of tumor xenografts derived from esophageal cancer cells with acquired 5-FU resistance to chemotherapeutic drugs was significantly abrogated by wortmannin treatment in animals. In summary, our data support PI3K/AKT as a valid therapeutic target and strongly suggest that PI3K/AKT inhibitors used in conjunction with conventional chemotherapy may be a potentially useful therapeutic strategy in treating esophageal cancer patients. Impact Journals LLC 2014-10-18 /pmc/articles/PMC4294385/ /pubmed/25344912 Text en Copyright: © 2014 Li et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Li, Bin Li, Jin Xu, Wen Wen Guan, Xin Yuan Qin, Yan Ru Zhang, Li Yi Law, Simon Tsao, Sai Wah Cheung, Annie L.M. Suppression of esophageal tumor growth and chemoresistance by directly targeting the PI3K/AKT pathway |
title | Suppression of esophageal tumor growth and chemoresistance by directly targeting the PI3K/AKT pathway |
title_full | Suppression of esophageal tumor growth and chemoresistance by directly targeting the PI3K/AKT pathway |
title_fullStr | Suppression of esophageal tumor growth and chemoresistance by directly targeting the PI3K/AKT pathway |
title_full_unstemmed | Suppression of esophageal tumor growth and chemoresistance by directly targeting the PI3K/AKT pathway |
title_short | Suppression of esophageal tumor growth and chemoresistance by directly targeting the PI3K/AKT pathway |
title_sort | suppression of esophageal tumor growth and chemoresistance by directly targeting the pi3k/akt pathway |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4294385/ https://www.ncbi.nlm.nih.gov/pubmed/25344912 |
work_keys_str_mv | AT libin suppressionofesophagealtumorgrowthandchemoresistancebydirectlytargetingthepi3kaktpathway AT lijin suppressionofesophagealtumorgrowthandchemoresistancebydirectlytargetingthepi3kaktpathway AT xuwenwen suppressionofesophagealtumorgrowthandchemoresistancebydirectlytargetingthepi3kaktpathway AT guanxinyuan suppressionofesophagealtumorgrowthandchemoresistancebydirectlytargetingthepi3kaktpathway AT qinyanru suppressionofesophagealtumorgrowthandchemoresistancebydirectlytargetingthepi3kaktpathway AT zhangliyi suppressionofesophagealtumorgrowthandchemoresistancebydirectlytargetingthepi3kaktpathway AT lawsimon suppressionofesophagealtumorgrowthandchemoresistancebydirectlytargetingthepi3kaktpathway AT tsaosaiwah suppressionofesophagealtumorgrowthandchemoresistancebydirectlytargetingthepi3kaktpathway AT cheungannielm suppressionofesophagealtumorgrowthandchemoresistancebydirectlytargetingthepi3kaktpathway |