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Role of nitric oxide in pancreatic cancer cells exhibiting the invasive phenotype

Pancreatic cancer is a highly metastatic tumor with an extremely low 5-year survival rate. Lack of efficient diagnostics and dearth of effective therapeutics that can target the cancer as well as the microenvironment niche are the reasons for limited success in treatment and management of this disea...

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Autores principales: Fujita, Mayumi, Somasundaram, Veena, Basudhar, Debashree, Cheng, Robert Y.S., Ridnour, Lisa A., Higuchi, Harumi, Imadome, Kaori, No, Jae Hong, Bharadwaj, Gaurav, Wink, David A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6409427/
https://www.ncbi.nlm.nih.gov/pubmed/30852389
http://dx.doi.org/10.1016/j.redox.2019.101158
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author Fujita, Mayumi
Somasundaram, Veena
Basudhar, Debashree
Cheng, Robert Y.S.
Ridnour, Lisa A.
Higuchi, Harumi
Imadome, Kaori
No, Jae Hong
Bharadwaj, Gaurav
Wink, David A.
author_facet Fujita, Mayumi
Somasundaram, Veena
Basudhar, Debashree
Cheng, Robert Y.S.
Ridnour, Lisa A.
Higuchi, Harumi
Imadome, Kaori
No, Jae Hong
Bharadwaj, Gaurav
Wink, David A.
author_sort Fujita, Mayumi
collection PubMed
description Pancreatic cancer is a highly metastatic tumor with an extremely low 5-year survival rate. Lack of efficient diagnostics and dearth of effective therapeutics that can target the cancer as well as the microenvironment niche are the reasons for limited success in treatment and management of this disease. Cell invasion through extracellular matrix (ECM) involves the complex regulation of adhesion to and detachment from ECM and its understanding is critical to metastatic potential of pancreatic cancer. To understand the characteristics of these cancer cells and their ability to metastasize, we compared human pancreatic cancer cell line, PANC-1 and its invading phenotype (INV) collected from transwell inserts. The invasive cell type, INV, exhibited higher resistance to Carbon-ion radiation compared to whole cultured (normally dish-cultured) PANC-1 (WCC), and had more efficient in vitro spheroid formation capability. Invasiveness of INV was hampered by nitric oxide synthase (NOS) inhibitors, suggesting that nitric oxide (NO) plays a cardinal role in PANC-1 invasion. In addition, in vitro studies indicated that a MEK-ERK-dependent, JAK independent mechanism through which NOS/NO modulate PANC-1 invasiveness. Suspended INV showed enhanced NO production as well as induction of several pro-metastatic, and stemness-related genes. NOS inhibitor, l-NAME, reduced the expression of these pro-metastatic or stemness-related genes, and dampened spheroid formation ability, suggesting that NO can potentially influence pancreatic cancer aggressiveness. Furthermore, xenograft studies with INV and WCC in NSG mouse model revealed a greater ability of INV compared to WCC, to metastasize to the liver and l-NAME diminished the metastatic lesions in mice injected with INV. Overall, data suggest that NO is a key player associated with resistance to radiation and metastasis of pancreatic cancer; and inhibition of NOS demonstrates therapeutic potential as observed in the animal model by specifically targeting the metastatic cells that harbor stem-like features and are potentially responsible for relapse.
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spelling pubmed-64094272019-03-21 Role of nitric oxide in pancreatic cancer cells exhibiting the invasive phenotype Fujita, Mayumi Somasundaram, Veena Basudhar, Debashree Cheng, Robert Y.S. Ridnour, Lisa A. Higuchi, Harumi Imadome, Kaori No, Jae Hong Bharadwaj, Gaurav Wink, David A. Redox Biol Research Paper Pancreatic cancer is a highly metastatic tumor with an extremely low 5-year survival rate. Lack of efficient diagnostics and dearth of effective therapeutics that can target the cancer as well as the microenvironment niche are the reasons for limited success in treatment and management of this disease. Cell invasion through extracellular matrix (ECM) involves the complex regulation of adhesion to and detachment from ECM and its understanding is critical to metastatic potential of pancreatic cancer. To understand the characteristics of these cancer cells and their ability to metastasize, we compared human pancreatic cancer cell line, PANC-1 and its invading phenotype (INV) collected from transwell inserts. The invasive cell type, INV, exhibited higher resistance to Carbon-ion radiation compared to whole cultured (normally dish-cultured) PANC-1 (WCC), and had more efficient in vitro spheroid formation capability. Invasiveness of INV was hampered by nitric oxide synthase (NOS) inhibitors, suggesting that nitric oxide (NO) plays a cardinal role in PANC-1 invasion. In addition, in vitro studies indicated that a MEK-ERK-dependent, JAK independent mechanism through which NOS/NO modulate PANC-1 invasiveness. Suspended INV showed enhanced NO production as well as induction of several pro-metastatic, and stemness-related genes. NOS inhibitor, l-NAME, reduced the expression of these pro-metastatic or stemness-related genes, and dampened spheroid formation ability, suggesting that NO can potentially influence pancreatic cancer aggressiveness. Furthermore, xenograft studies with INV and WCC in NSG mouse model revealed a greater ability of INV compared to WCC, to metastasize to the liver and l-NAME diminished the metastatic lesions in mice injected with INV. Overall, data suggest that NO is a key player associated with resistance to radiation and metastasis of pancreatic cancer; and inhibition of NOS demonstrates therapeutic potential as observed in the animal model by specifically targeting the metastatic cells that harbor stem-like features and are potentially responsible for relapse. Elsevier 2019-03-06 /pmc/articles/PMC6409427/ /pubmed/30852389 http://dx.doi.org/10.1016/j.redox.2019.101158 Text en © 2019 Published by Elsevier B.V. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Paper
Fujita, Mayumi
Somasundaram, Veena
Basudhar, Debashree
Cheng, Robert Y.S.
Ridnour, Lisa A.
Higuchi, Harumi
Imadome, Kaori
No, Jae Hong
Bharadwaj, Gaurav
Wink, David A.
Role of nitric oxide in pancreatic cancer cells exhibiting the invasive phenotype
title Role of nitric oxide in pancreatic cancer cells exhibiting the invasive phenotype
title_full Role of nitric oxide in pancreatic cancer cells exhibiting the invasive phenotype
title_fullStr Role of nitric oxide in pancreatic cancer cells exhibiting the invasive phenotype
title_full_unstemmed Role of nitric oxide in pancreatic cancer cells exhibiting the invasive phenotype
title_short Role of nitric oxide in pancreatic cancer cells exhibiting the invasive phenotype
title_sort role of nitric oxide in pancreatic cancer cells exhibiting the invasive phenotype
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6409427/
https://www.ncbi.nlm.nih.gov/pubmed/30852389
http://dx.doi.org/10.1016/j.redox.2019.101158
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