constitutive and treatment-induced cxcl8-signalling selectively modulates the efficacy of anti-metabolite therapeutics in metastatic prostate cancer本构和treatment-induced cxcl8-signalling选择性地调节anti-metabolite治疗在转移性前列腺癌的功效.pdf
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Constitutive and Treatment-Induced CXCL8-Signalling
Selectively Modulates the Efficacy of Anti-Metabolite
Therapeutics in Metastatic Prostate Cancer
Catherine Wilson., Pamela J. Maxwell., Daniel B. Longley, Richard H. Wilson, Patrick G. Johnston,
David J. J. Waugh*
Centre for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast, Northern Ireland
Abstract
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,
A 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 A 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
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