Cargando…
Synergistic apoptosis following endoplasmic reticulum stress aggravation in mucinous colon cancer
BACKGROUND: Mucinous colon cancers (MCC) are characterized by abundant production of mucin 2 (MUC2) protein and are less sensitive to standard systemic chemotherapy. We postulated that severe/persistent endoplasmic reticulum stress (ERS) aggravation in MCC would overwhelm compensatory cytoprotective...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7437176/ https://www.ncbi.nlm.nih.gov/pubmed/32811515 http://dx.doi.org/10.1186/s13023-020-01499-1 |
_version_ | 1783572608077266944 |
---|---|
author | Dilly, Ashok K. Honick, Brendon D. Lee, Yong J. Bartlett, David L. Choudry, Haroon A. |
author_facet | Dilly, Ashok K. Honick, Brendon D. Lee, Yong J. Bartlett, David L. Choudry, Haroon A. |
author_sort | Dilly, Ashok K. |
collection | PubMed |
description | BACKGROUND: Mucinous colon cancers (MCC) are characterized by abundant production of mucin 2 (MUC2) protein and are less sensitive to standard systemic chemotherapy. We postulated that severe/persistent endoplasmic reticulum stress (ERS) aggravation in MCC would overwhelm compensatory cytoprotective pathways and induce apoptosis. RESULTS: Basal levels of ERS markers were higher in MCC and dnTCF-LS174T cells than non-mucinous tumors and these levels were significantly increased by combinatorial treatment with ERS aggravators celecoxib + orlistat. Combination treatment inhibited cell viability and synergistically induced apoptosis. Treatment-induced cell death was ERS-dependent, apoptotic pathways were not activated following knockdown of ERS protein CHOP. Dual drug treatment significantly reduced mucinous tumor growth in vivo and induced ERS and apoptosis, consistent with in vitro experiments. CONCLUSIONS: Novel therapies are needed since MCC are more resistant to standard systemic chemotherapy. This study suggests ERS aggravation is a viable therapeutic strategy to reduce tumor growth in MCC. |
format | Online Article Text |
id | pubmed-7437176 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-74371762020-08-24 Synergistic apoptosis following endoplasmic reticulum stress aggravation in mucinous colon cancer Dilly, Ashok K. Honick, Brendon D. Lee, Yong J. Bartlett, David L. Choudry, Haroon A. Orphanet J Rare Dis Research BACKGROUND: Mucinous colon cancers (MCC) are characterized by abundant production of mucin 2 (MUC2) protein and are less sensitive to standard systemic chemotherapy. We postulated that severe/persistent endoplasmic reticulum stress (ERS) aggravation in MCC would overwhelm compensatory cytoprotective pathways and induce apoptosis. RESULTS: Basal levels of ERS markers were higher in MCC and dnTCF-LS174T cells than non-mucinous tumors and these levels were significantly increased by combinatorial treatment with ERS aggravators celecoxib + orlistat. Combination treatment inhibited cell viability and synergistically induced apoptosis. Treatment-induced cell death was ERS-dependent, apoptotic pathways were not activated following knockdown of ERS protein CHOP. Dual drug treatment significantly reduced mucinous tumor growth in vivo and induced ERS and apoptosis, consistent with in vitro experiments. CONCLUSIONS: Novel therapies are needed since MCC are more resistant to standard systemic chemotherapy. This study suggests ERS aggravation is a viable therapeutic strategy to reduce tumor growth in MCC. BioMed Central 2020-08-18 /pmc/articles/PMC7437176/ /pubmed/32811515 http://dx.doi.org/10.1186/s13023-020-01499-1 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Dilly, Ashok K. Honick, Brendon D. Lee, Yong J. Bartlett, David L. Choudry, Haroon A. Synergistic apoptosis following endoplasmic reticulum stress aggravation in mucinous colon cancer |
title | Synergistic apoptosis following endoplasmic reticulum stress aggravation in mucinous colon cancer |
title_full | Synergistic apoptosis following endoplasmic reticulum stress aggravation in mucinous colon cancer |
title_fullStr | Synergistic apoptosis following endoplasmic reticulum stress aggravation in mucinous colon cancer |
title_full_unstemmed | Synergistic apoptosis following endoplasmic reticulum stress aggravation in mucinous colon cancer |
title_short | Synergistic apoptosis following endoplasmic reticulum stress aggravation in mucinous colon cancer |
title_sort | synergistic apoptosis following endoplasmic reticulum stress aggravation in mucinous colon cancer |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7437176/ https://www.ncbi.nlm.nih.gov/pubmed/32811515 http://dx.doi.org/10.1186/s13023-020-01499-1 |
work_keys_str_mv | AT dillyashokk synergisticapoptosisfollowingendoplasmicreticulumstressaggravationinmucinouscoloncancer AT honickbrendond synergisticapoptosisfollowingendoplasmicreticulumstressaggravationinmucinouscoloncancer AT leeyongj synergisticapoptosisfollowingendoplasmicreticulumstressaggravationinmucinouscoloncancer AT bartlettdavidl synergisticapoptosisfollowingendoplasmicreticulumstressaggravationinmucinouscoloncancer AT choudryharoona synergisticapoptosisfollowingendoplasmicreticulumstressaggravationinmucinouscoloncancer |