Cargando…
Inflammatory cytokine production in tumor cells upon chemotherapy drug exposure or upon selection for drug resistance
Tumor Necrosis Factor alpha (TNF-α) has been shown to be released by tumor cells in response to docetaxel, and lipopolysaccharides (LPS), the latter through activation of toll-like receptor 4 (TLR4). However, it is unclear whether the former involves TLR4 receptor activation through direct binding o...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2017
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5600395/ https://www.ncbi.nlm.nih.gov/pubmed/28915246 http://dx.doi.org/10.1371/journal.pone.0183662 |
_version_ | 1783264234738548736 |
---|---|
author | Edwardson, Derek W. Boudreau, Justin Mapletoft, Jonathan Lanner, Carita Kovala, A. Thomas Parissenti, Amadeo M. |
author_facet | Edwardson, Derek W. Boudreau, Justin Mapletoft, Jonathan Lanner, Carita Kovala, A. Thomas Parissenti, Amadeo M. |
author_sort | Edwardson, Derek W. |
collection | PubMed |
description | Tumor Necrosis Factor alpha (TNF-α) has been shown to be released by tumor cells in response to docetaxel, and lipopolysaccharides (LPS), the latter through activation of toll-like receptor 4 (TLR4). However, it is unclear whether the former involves TLR4 receptor activation through direct binding of the drug to TLR4 at the cell surface. The current study was intended to better understand drug-induced TNF-α production in tumor cells, whether from short-term drug exposure or in cells selected for drug resistance. ELISAs were employed to measure cytokine release from breast and ovarian tumor cells in response to several structurally distinct chemotherapy agents and/or TLR4 agonists or antagonists. Drug uptake and drug sensitivity studies were also performed. We observed that several drugs induced TNF-αrelease from multiple tumor cell lines. Docetaxel-induced cytokine production was distinct from that of LPS in both MyD88-positive (MCF-7) and MyD88-deficient (A2780) cells. The acquisition of docetaxel resistance was accompanied by increased constitutive production of TNF-αand CXCL1, which waned at higher levels of resistance. In docetaxel-resistant MCF-7 and A2780 cell lines, the production of TNF-α could not be significantly augmented by docetaxel without the inhibition of P-gp, a transporter protein that promotes drug efflux from tumor cells. Pretreatment of tumor cells with LPS sensitized MyD88-positive cells (but not MyD88-deficient) to docetaxel cytotoxicity in both drug-naive and drug-resistant cells. Our findings suggest that taxane-induced inflammatory cytokine production from tumor cells depends on the duration of exposure, requires cellular drug-accumulation, and is distinct from the LPS response seen in breast tumor cells. Also, stimulation of the LPS-induced pathway may be an attractive target for treatment of drug-resistant disease. |
format | Online Article Text |
id | pubmed-5600395 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-56003952017-09-22 Inflammatory cytokine production in tumor cells upon chemotherapy drug exposure or upon selection for drug resistance Edwardson, Derek W. Boudreau, Justin Mapletoft, Jonathan Lanner, Carita Kovala, A. Thomas Parissenti, Amadeo M. PLoS One Research Article Tumor Necrosis Factor alpha (TNF-α) has been shown to be released by tumor cells in response to docetaxel, and lipopolysaccharides (LPS), the latter through activation of toll-like receptor 4 (TLR4). However, it is unclear whether the former involves TLR4 receptor activation through direct binding of the drug to TLR4 at the cell surface. The current study was intended to better understand drug-induced TNF-α production in tumor cells, whether from short-term drug exposure or in cells selected for drug resistance. ELISAs were employed to measure cytokine release from breast and ovarian tumor cells in response to several structurally distinct chemotherapy agents and/or TLR4 agonists or antagonists. Drug uptake and drug sensitivity studies were also performed. We observed that several drugs induced TNF-αrelease from multiple tumor cell lines. Docetaxel-induced cytokine production was distinct from that of LPS in both MyD88-positive (MCF-7) and MyD88-deficient (A2780) cells. The acquisition of docetaxel resistance was accompanied by increased constitutive production of TNF-αand CXCL1, which waned at higher levels of resistance. In docetaxel-resistant MCF-7 and A2780 cell lines, the production of TNF-α could not be significantly augmented by docetaxel without the inhibition of P-gp, a transporter protein that promotes drug efflux from tumor cells. Pretreatment of tumor cells with LPS sensitized MyD88-positive cells (but not MyD88-deficient) to docetaxel cytotoxicity in both drug-naive and drug-resistant cells. Our findings suggest that taxane-induced inflammatory cytokine production from tumor cells depends on the duration of exposure, requires cellular drug-accumulation, and is distinct from the LPS response seen in breast tumor cells. Also, stimulation of the LPS-induced pathway may be an attractive target for treatment of drug-resistant disease. Public Library of Science 2017-09-15 /pmc/articles/PMC5600395/ /pubmed/28915246 http://dx.doi.org/10.1371/journal.pone.0183662 Text en © 2017 Edwardson 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 (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Edwardson, Derek W. Boudreau, Justin Mapletoft, Jonathan Lanner, Carita Kovala, A. Thomas Parissenti, Amadeo M. Inflammatory cytokine production in tumor cells upon chemotherapy drug exposure or upon selection for drug resistance |
title | Inflammatory cytokine production in tumor cells upon chemotherapy drug exposure or upon selection for drug resistance |
title_full | Inflammatory cytokine production in tumor cells upon chemotherapy drug exposure or upon selection for drug resistance |
title_fullStr | Inflammatory cytokine production in tumor cells upon chemotherapy drug exposure or upon selection for drug resistance |
title_full_unstemmed | Inflammatory cytokine production in tumor cells upon chemotherapy drug exposure or upon selection for drug resistance |
title_short | Inflammatory cytokine production in tumor cells upon chemotherapy drug exposure or upon selection for drug resistance |
title_sort | inflammatory cytokine production in tumor cells upon chemotherapy drug exposure or upon selection for drug resistance |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5600395/ https://www.ncbi.nlm.nih.gov/pubmed/28915246 http://dx.doi.org/10.1371/journal.pone.0183662 |
work_keys_str_mv | AT edwardsonderekw inflammatorycytokineproductionintumorcellsuponchemotherapydrugexposureoruponselectionfordrugresistance AT boudreaujustin inflammatorycytokineproductionintumorcellsuponchemotherapydrugexposureoruponselectionfordrugresistance AT mapletoftjonathan inflammatorycytokineproductionintumorcellsuponchemotherapydrugexposureoruponselectionfordrugresistance AT lannercarita inflammatorycytokineproductionintumorcellsuponchemotherapydrugexposureoruponselectionfordrugresistance AT kovalaathomas inflammatorycytokineproductionintumorcellsuponchemotherapydrugexposureoruponselectionfordrugresistance AT parissentiamadeom inflammatorycytokineproductionintumorcellsuponchemotherapydrugexposureoruponselectionfordrugresistance |