Constitutive and treatment-induced CXCL8-signalling selectively modulates the efficacy of anti-metabolite therapeutics in metastatic prostate cancer.
BACKGROUND:The current study was undertaken to characterize the effect of anti-metabolites on inducing CXCL8 signaling and determining whether the constitutive and/or drug-induced CXCL8 signaling in metastatic prostate cancer (CaP) cells modulates their sensitivity to this class of agent. METHODS:Th...
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doaj-df5e2fe21e244201859886790dca0e372020-11-24T21:47:57ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0175e3654510.1371/journal.pone.0036545Constitutive and treatment-induced CXCL8-signalling selectively modulates the efficacy of anti-metabolite therapeutics in metastatic prostate cancer.Catherine WilsonPamela J MaxwellDaniel B LongleyRichard H WilsonPatrick G JohnstonDavid J J WaughBACKGROUND:The current study was undertaken to characterize the effect of anti-metabolites on inducing CXCL8 signaling and determining whether the constitutive and/or drug-induced CXCL8 signaling in metastatic prostate cancer (CaP) cells modulates their sensitivity to this class of agent. METHODS:The response of metastatic CaP cells to 5-Fluorouracil (5-FU), Pemetrexed or Tomudex was determined using cell count assays, flow cytometry and PARP cleavage analysis. Quantitative-PCR, ELISA and immunoblots were employed to determine effects of drugs or CXCL8 administration on target gene/protein expression. RESULTS:Administration of 5-FU but not pemetrexed potentiated CXCL8 secretion and increased CXCR1 and CXCR2 gene expression in metastatic PC3 cells. Consistent with this, the inhibition of CXCL8 signaling using a CXCR2 antagonist, AZ10397767, increased the cytotoxicity of 5-FU by 4-fold (P<0.001), and increased 5-FU-induced apoptosis in PC3 cells (P<0.01). In contrast, while administration of AZ10397767 had no effect on the sensitivity of pemetrexed, the CXCR2 antagonist exerted the greatest effect in increasing the sensitivity of PC3 cells to Tomudex, a directed thymidylate synthase (TS) inhibitor. Subsequent experiments confirmed that administration of recombinant human CXCL8 increased TS expression, a response mediated in part by the CXCR2 receptor. Moreover, siRNA-mediated knockdown of the CXCL8-target gene Bcl-2 increased the sensitivity of PC3 cells to 5-FU. CONCLUSIONS:CXCL8 signaling provides a selective resistance of metastatic prostate cancer cells to specific anti-metabolites by promoting a target-associated resistance, in addition to underpinning an evasion of treatment-induced apoptosis.http://europepmc.org/articles/PMC3348872?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Catherine Wilson Pamela J Maxwell Daniel B Longley Richard H Wilson Patrick G Johnston David J J Waugh |
spellingShingle |
Catherine Wilson Pamela J Maxwell Daniel B Longley Richard H Wilson Patrick G Johnston David J J Waugh Constitutive and treatment-induced CXCL8-signalling selectively modulates the efficacy of anti-metabolite therapeutics in metastatic prostate cancer. PLoS ONE |
author_facet |
Catherine Wilson Pamela J Maxwell Daniel B Longley Richard H Wilson Patrick G Johnston David J J Waugh |
author_sort |
Catherine Wilson |
title |
Constitutive and treatment-induced CXCL8-signalling selectively modulates the efficacy of anti-metabolite therapeutics in metastatic prostate cancer. |
title_short |
Constitutive and treatment-induced CXCL8-signalling selectively modulates the efficacy of anti-metabolite therapeutics in metastatic prostate cancer. |
title_full |
Constitutive and treatment-induced CXCL8-signalling selectively modulates the efficacy of anti-metabolite therapeutics in metastatic prostate cancer. |
title_fullStr |
Constitutive and treatment-induced CXCL8-signalling selectively modulates the efficacy of anti-metabolite therapeutics in metastatic prostate cancer. |
title_full_unstemmed |
Constitutive and treatment-induced CXCL8-signalling selectively modulates the efficacy of anti-metabolite therapeutics in metastatic prostate cancer. |
title_sort |
constitutive and treatment-induced cxcl8-signalling selectively modulates the efficacy of anti-metabolite therapeutics in metastatic prostate cancer. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2012-01-01 |
description |
BACKGROUND:The current study was undertaken to characterize the effect of anti-metabolites on inducing CXCL8 signaling and determining whether the constitutive and/or drug-induced CXCL8 signaling in metastatic prostate cancer (CaP) cells modulates their sensitivity to this class of agent. METHODS:The response of metastatic CaP cells to 5-Fluorouracil (5-FU), Pemetrexed or Tomudex was determined using cell count assays, flow cytometry and PARP cleavage analysis. Quantitative-PCR, ELISA and immunoblots were employed to determine effects of drugs or CXCL8 administration on target gene/protein expression. RESULTS:Administration of 5-FU but not pemetrexed potentiated CXCL8 secretion and increased CXCR1 and CXCR2 gene expression in metastatic PC3 cells. Consistent with this, the inhibition of CXCL8 signaling using a CXCR2 antagonist, AZ10397767, increased the cytotoxicity of 5-FU by 4-fold (P<0.001), and increased 5-FU-induced apoptosis in PC3 cells (P<0.01). In contrast, while administration of AZ10397767 had no effect on the sensitivity of pemetrexed, the CXCR2 antagonist exerted the greatest effect in increasing the sensitivity of PC3 cells to Tomudex, a directed thymidylate synthase (TS) inhibitor. Subsequent experiments confirmed that administration of recombinant human CXCL8 increased TS expression, a response mediated in part by the CXCR2 receptor. Moreover, siRNA-mediated knockdown of the CXCL8-target gene Bcl-2 increased the sensitivity of PC3 cells to 5-FU. CONCLUSIONS:CXCL8 signaling provides a selective resistance of metastatic prostate cancer cells to specific anti-metabolites by promoting a target-associated resistance, in addition to underpinning an evasion of treatment-induced apoptosis. |
url |
http://europepmc.org/articles/PMC3348872?pdf=render |
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