Cargando…
The Roles of ROS and Caspases in TRAIL-Induced Apoptosis and Necroptosis in Human Pancreatic Cancer Cells
Death signaling provided by tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) can induce death in cancer cells with little cytotoxicity to normal cells; this cell death has been thought to involve caspase-dependent apoptosis. Reactive oxygen species (ROS) are also mediators that...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2015
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4441514/ https://www.ncbi.nlm.nih.gov/pubmed/26000607 http://dx.doi.org/10.1371/journal.pone.0127386 |
_version_ | 1782372808609759232 |
---|---|
author | Zhang, Min Harashima, Nanae Moritani, Tamami Huang, Weidong Harada, Mamoru |
author_facet | Zhang, Min Harashima, Nanae Moritani, Tamami Huang, Weidong Harada, Mamoru |
author_sort | Zhang, Min |
collection | PubMed |
description | Death signaling provided by tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) can induce death in cancer cells with little cytotoxicity to normal cells; this cell death has been thought to involve caspase-dependent apoptosis. Reactive oxygen species (ROS) are also mediators that induce cell death, but their roles in TRAIL-induced apoptosis have not been elucidated fully. In the current study, we investigated ROS and caspases in human pancreatic cancer cells undergoing two different types of TRAIL-induced cell death, apoptosis and necroptosis. TRAIL treatment increased ROS in two TRAIL-sensitive pancreatic cancer cell lines, MiaPaCa-2 and BxPC-3, but ROS were involved in TRAIL-induced apoptosis only in MiaPaCa-2 cells. Unexpectedly, inhibition of ROS by either N-acetyl-L-cysteine (NAC), a peroxide inhibitor, or Tempol, a superoxide inhibitor, increased the annexin V-/propidium iodide (PI)(+) early necrotic population in TRAIL-treated cells. Additionally, both necrostatin-1, an inhibitor of receptor-interacting protein kinase 1 (RIP1), and siRNA-mediated knockdown of RIP3 decreased the annexin V(-)/PI(+) early necrotic population after TRAIL treatment. Furthermore, an increase in early apoptosis was induced in TRAIL-treated cancer cells under inhibition of either caspase-2 or -9. Caspase-2 worked upstream of caspase-9, and no crosstalk was observed between ROS and caspase-2/-9 in TRAIL-treated cells. Together, these results indicate that ROS contribute to TRAIL-induced apoptosis in MiaPaCa-2 cells, and that ROS play an inhibitory role in TRAIL-induced necroptosis of MiaPaCa-2 and BxPC-3 cells, with caspase-2 and -9 playing regulatory roles in this process. |
format | Online Article Text |
id | pubmed-4441514 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-44415142015-05-28 The Roles of ROS and Caspases in TRAIL-Induced Apoptosis and Necroptosis in Human Pancreatic Cancer Cells Zhang, Min Harashima, Nanae Moritani, Tamami Huang, Weidong Harada, Mamoru PLoS One Research Article Death signaling provided by tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) can induce death in cancer cells with little cytotoxicity to normal cells; this cell death has been thought to involve caspase-dependent apoptosis. Reactive oxygen species (ROS) are also mediators that induce cell death, but their roles in TRAIL-induced apoptosis have not been elucidated fully. In the current study, we investigated ROS and caspases in human pancreatic cancer cells undergoing two different types of TRAIL-induced cell death, apoptosis and necroptosis. TRAIL treatment increased ROS in two TRAIL-sensitive pancreatic cancer cell lines, MiaPaCa-2 and BxPC-3, but ROS were involved in TRAIL-induced apoptosis only in MiaPaCa-2 cells. Unexpectedly, inhibition of ROS by either N-acetyl-L-cysteine (NAC), a peroxide inhibitor, or Tempol, a superoxide inhibitor, increased the annexin V-/propidium iodide (PI)(+) early necrotic population in TRAIL-treated cells. Additionally, both necrostatin-1, an inhibitor of receptor-interacting protein kinase 1 (RIP1), and siRNA-mediated knockdown of RIP3 decreased the annexin V(-)/PI(+) early necrotic population after TRAIL treatment. Furthermore, an increase in early apoptosis was induced in TRAIL-treated cancer cells under inhibition of either caspase-2 or -9. Caspase-2 worked upstream of caspase-9, and no crosstalk was observed between ROS and caspase-2/-9 in TRAIL-treated cells. Together, these results indicate that ROS contribute to TRAIL-induced apoptosis in MiaPaCa-2 cells, and that ROS play an inhibitory role in TRAIL-induced necroptosis of MiaPaCa-2 and BxPC-3 cells, with caspase-2 and -9 playing regulatory roles in this process. Public Library of Science 2015-05-22 /pmc/articles/PMC4441514/ /pubmed/26000607 http://dx.doi.org/10.1371/journal.pone.0127386 Text en © 2015 Zhang et al http://creativecommons.org/licenses/by/4.0/ 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 properly credited. |
spellingShingle | Research Article Zhang, Min Harashima, Nanae Moritani, Tamami Huang, Weidong Harada, Mamoru The Roles of ROS and Caspases in TRAIL-Induced Apoptosis and Necroptosis in Human Pancreatic Cancer Cells |
title | The Roles of ROS and Caspases in TRAIL-Induced Apoptosis and Necroptosis in Human Pancreatic Cancer Cells |
title_full | The Roles of ROS and Caspases in TRAIL-Induced Apoptosis and Necroptosis in Human Pancreatic Cancer Cells |
title_fullStr | The Roles of ROS and Caspases in TRAIL-Induced Apoptosis and Necroptosis in Human Pancreatic Cancer Cells |
title_full_unstemmed | The Roles of ROS and Caspases in TRAIL-Induced Apoptosis and Necroptosis in Human Pancreatic Cancer Cells |
title_short | The Roles of ROS and Caspases in TRAIL-Induced Apoptosis and Necroptosis in Human Pancreatic Cancer Cells |
title_sort | roles of ros and caspases in trail-induced apoptosis and necroptosis in human pancreatic cancer cells |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4441514/ https://www.ncbi.nlm.nih.gov/pubmed/26000607 http://dx.doi.org/10.1371/journal.pone.0127386 |
work_keys_str_mv | AT zhangmin therolesofrosandcaspasesintrailinducedapoptosisandnecroptosisinhumanpancreaticcancercells AT harashimananae therolesofrosandcaspasesintrailinducedapoptosisandnecroptosisinhumanpancreaticcancercells AT moritanitamami therolesofrosandcaspasesintrailinducedapoptosisandnecroptosisinhumanpancreaticcancercells AT huangweidong therolesofrosandcaspasesintrailinducedapoptosisandnecroptosisinhumanpancreaticcancercells AT haradamamoru therolesofrosandcaspasesintrailinducedapoptosisandnecroptosisinhumanpancreaticcancercells AT zhangmin rolesofrosandcaspasesintrailinducedapoptosisandnecroptosisinhumanpancreaticcancercells AT harashimananae rolesofrosandcaspasesintrailinducedapoptosisandnecroptosisinhumanpancreaticcancercells AT moritanitamami rolesofrosandcaspasesintrailinducedapoptosisandnecroptosisinhumanpancreaticcancercells AT huangweidong rolesofrosandcaspasesintrailinducedapoptosisandnecroptosisinhumanpancreaticcancercells AT haradamamoru rolesofrosandcaspasesintrailinducedapoptosisandnecroptosisinhumanpancreaticcancercells |