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Crizotinib Exhibits Antitumor Activity by Targeting ALK Signaling not c-MET in Pancreatic Cancer

Crizotinib, a c-MET/ALK inhibitor, has exhibited antitumor efficacy in different types of cancers. However, studies regarding Crizotinib in pancreatic cancer have been limited. Thus, we investigated the effect of Crizotinib on pancreatic cancer and its mechanism of action. Crizotinib strongly suppre...

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Autores principales: Yan, Hong Hua, Jung, Kyung Hee, Son, Mi Kwon, Fang, Zhenghuan, Kim, Soo Jung, Ryu, Ye-Lim, Kim, Juyoung, Kim, Mi-Hyun, Hong, Soon-Sun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4253425/
https://www.ncbi.nlm.nih.gov/pubmed/25193856
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author Yan, Hong Hua
Jung, Kyung Hee
Son, Mi Kwon
Fang, Zhenghuan
Kim, Soo Jung
Ryu, Ye-Lim
Kim, Juyoung
Kim, Mi-Hyun
Hong, Soon-Sun
author_facet Yan, Hong Hua
Jung, Kyung Hee
Son, Mi Kwon
Fang, Zhenghuan
Kim, Soo Jung
Ryu, Ye-Lim
Kim, Juyoung
Kim, Mi-Hyun
Hong, Soon-Sun
author_sort Yan, Hong Hua
collection PubMed
description Crizotinib, a c-MET/ALK inhibitor, has exhibited antitumor efficacy in different types of cancers. However, studies regarding Crizotinib in pancreatic cancer have been limited. Thus, we investigated the effect of Crizotinib on pancreatic cancer and its mechanism of action. Crizotinib strongly suppressed the growth and proliferation of pancreatic cancer cells in a dose-dependent manner. Also, it induced apoptosis by modulating its related factors. In the study, with regard to the mechanism of action, Crizotinib did not inhibit c-MET expression on pancreatic cancer cells; instead, it specifically inhibited the activity of ALK, which was identified to be highly expressed on various pancreatic cancer cells and tissues in our study. In 42 different receptor tyrosine kinase (RTKs) array, Crizotinib also strongly inhibited the expression of activated ALK in pancreatic cancer cells, modulating its downstream mediators such as STAT3, AKT, and ERK. Furthermore, Crizotinib inhibited angiogenesis in a mouse Matrigel plug assay as well as the progression of tumor growth in a mouse xenograft model. Taken together, our investigation shows that Crizotinib inhibits the ALK signaling pathway in pancreatic cancer, resulting in cell growth/angiogenesis inhibition and apoptosis induction. We suggest that Crizotinib might be used as a novel therapeutic drug for treating pancreatic cancer.
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spelling pubmed-42534252014-12-03 Crizotinib Exhibits Antitumor Activity by Targeting ALK Signaling not c-MET in Pancreatic Cancer Yan, Hong Hua Jung, Kyung Hee Son, Mi Kwon Fang, Zhenghuan Kim, Soo Jung Ryu, Ye-Lim Kim, Juyoung Kim, Mi-Hyun Hong, Soon-Sun Oncotarget Research Paper Crizotinib, a c-MET/ALK inhibitor, has exhibited antitumor efficacy in different types of cancers. However, studies regarding Crizotinib in pancreatic cancer have been limited. Thus, we investigated the effect of Crizotinib on pancreatic cancer and its mechanism of action. Crizotinib strongly suppressed the growth and proliferation of pancreatic cancer cells in a dose-dependent manner. Also, it induced apoptosis by modulating its related factors. In the study, with regard to the mechanism of action, Crizotinib did not inhibit c-MET expression on pancreatic cancer cells; instead, it specifically inhibited the activity of ALK, which was identified to be highly expressed on various pancreatic cancer cells and tissues in our study. In 42 different receptor tyrosine kinase (RTKs) array, Crizotinib also strongly inhibited the expression of activated ALK in pancreatic cancer cells, modulating its downstream mediators such as STAT3, AKT, and ERK. Furthermore, Crizotinib inhibited angiogenesis in a mouse Matrigel plug assay as well as the progression of tumor growth in a mouse xenograft model. Taken together, our investigation shows that Crizotinib inhibits the ALK signaling pathway in pancreatic cancer, resulting in cell growth/angiogenesis inhibition and apoptosis induction. We suggest that Crizotinib might be used as a novel therapeutic drug for treating pancreatic cancer. Impact Journals LLC 2014-08-23 /pmc/articles/PMC4253425/ /pubmed/25193856 Text en Copyright: © 2014 Yan 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
Yan, Hong Hua
Jung, Kyung Hee
Son, Mi Kwon
Fang, Zhenghuan
Kim, Soo Jung
Ryu, Ye-Lim
Kim, Juyoung
Kim, Mi-Hyun
Hong, Soon-Sun
Crizotinib Exhibits Antitumor Activity by Targeting ALK Signaling not c-MET in Pancreatic Cancer
title Crizotinib Exhibits Antitumor Activity by Targeting ALK Signaling not c-MET in Pancreatic Cancer
title_full Crizotinib Exhibits Antitumor Activity by Targeting ALK Signaling not c-MET in Pancreatic Cancer
title_fullStr Crizotinib Exhibits Antitumor Activity by Targeting ALK Signaling not c-MET in Pancreatic Cancer
title_full_unstemmed Crizotinib Exhibits Antitumor Activity by Targeting ALK Signaling not c-MET in Pancreatic Cancer
title_short Crizotinib Exhibits Antitumor Activity by Targeting ALK Signaling not c-MET in Pancreatic Cancer
title_sort crizotinib exhibits antitumor activity by targeting alk signaling not c-met in pancreatic cancer
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4253425/
https://www.ncbi.nlm.nih.gov/pubmed/25193856
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