Chemotherapy-Induced CXC-Chemokine/CXC-Chemokine Receptor Signaling in Metastatic Prostate Cancer Cells Confers Resistance to Oxaliplatin through Potentiation of Nuclear Factor-κB Transcription and Evasion of Apoptosis

Wilson, Catherine; Purcell, Colin; Seaton, Angela; Oladipo, O.; Maxwell, Pamela; O’Sullivan, Joe M.; Wilson, Richard H.; Johnston, Patrick G.; Waugh, David J.

doi:10.1124/jpet.108.143826

Cited by 101 publications

(104 citation statements)

References 33 publications

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“…However, co-administration of DEX was observed to attenuate the docetaxel-induced AP-1 and NF-kB transcriptional activity and abrogated docetaxel-induced CXC-chemokine gene transcription and secretion in PC3 cells and endothelial cells. We have recently reported that the induction of IL-8 signalling in hypoxic and normoxic CaP cell lines activates cell survival signalling and confers a survival advantage to these cells in response to DNAdamage agents (Maxwell et al, 2007;Wilson et al, 2008b), antiandrogens and biological inducers of apoptosis such as TNF-receptor apoptosis-inducing ligand (Wilson et al, 2008a). Direct inhibition of NF-kB using BAY11-7082 or direct antagonism of IL-8 signalling, targeting the ligand with a neutralising antibody or through a CXCR2-receptor antagonist, failed to potentiate the cytotoxicity of docetaxel in these cells.…”

Section: Discussionmentioning

confidence: 99%

Dexamethasone potentiates the antiangiogenic activity of docetaxel in castration-resistant prostate cancer

Wilson¹,

Scullin²,

Worthington³

et al. 2008

Br J Cancer

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We sought to characterise whether dexamethasone (DEX) may enhance tumour response to docetaxel in in vitro and in vivo models of metastatic prostate cancer (CaP). In vitro experiments conducted on PC3 and human bone marrow endothelial cells (hBMECs) determined that administration of DEX (10 nM) reduced constitutive nuclear factor-kB (NF-kB) activity, decreasing interleukin (IL)-8, CXCL1 and VEGF gene expression in PC3 cells. Dexamethasone also attenuated docetaxel-induced NF-kB and activator protein-1 transcription and reduced docetaxel-promoted expression/secretion of IL-8 and CXCL1 in PC3 and hBMECs. Although DEX failed to enhance docetaxel cytotoxicity on PC3 cells, DEX potentiated the antiangiogenic activity of docetaxel in vitro, further reducing vessel area and vessel length in developing endothelial tubes (Po0.05). Docetaxel had a potent antiangiogenic activity in the dorsal skin flap-implanted PC3 tumours in vivo. Small blood vessel formation was further suppressed in tumours co-treated with docetaxel and DEX, substantiated by an increased average vessel diameter and segment length and a decreased number of branch points in the residual tumour vasculature (Po0.001). Our data show that DEX potentiates the antiangiogenic activity of docetaxel, suggesting a putative mechanism for the palliative and survival benefits of these agents in metastatic CaP.

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Section: Discussionmentioning

confidence: 99%

Dexamethasone potentiates the antiangiogenic activity of docetaxel in castration-resistant prostate cancer

Wilson¹,

Scullin²,

Worthington³

et al. 2008

Br J Cancer

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“…To see whether MT1G expression altered this signaling pathway, we measured mRNA levels of two known NF-kB target genes involved in chemoresistance [interleukin (IL)-8 and CXCL1; ref. 25] after OXA treatment of MOCK and MT1G þ cells. As shown in Fig.…”

Section: Chemotherapy Treatment Modulates Zinc Metabolismmentioning

confidence: 99%

Metallothionein 1G and Zinc Sensitize Human Colorectal Cancer Cells to Chemotherapy

Arriaga

Greco

Mordoh

et al. 2014

Molecular Cancer Therapeutics

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Metallothioneins (MT) are a family of low molecular weight proteins that are silenced during colorectal cancer progression, mainly through epigenetic mechanisms, and this loss is associated with poor survival. In this article, we show that overexpression of the MT1G isoform sensitizes colorectal cell lines to the chemotherapeutic agents oxaliplatin (OXA) and 5-fluorouracil (5-FU), in part through enhancing p53 and repressing NF-kB activity. Despite being silenced, MTs can be reinduced by histone deacetylase inhibitors such as trichostatin A and sodium butyrate. In fact, this induction contributes to the cytotoxicity of these agents, given that silencing of MTs by siRNAs reduces their growth-inhibitory activities. Zinc ions also potently enhance MT expression and are cytotoxic to cancer cells. We show for the first time that OXA and 5-FU induce higher levels of intracellular labile zinc, as measured using the fluorescent probe FLUOZIN-3, and that such zinc contributes to the activation of p53 and repression of NF-kB. Addition of zinc enhanced growth inhibition by OXA and 5-FU, and was also capable of resensitizing 5-FU-resistant cell lines to levels comparable with sensitive cell lines. This effect was MT independent because silencing MTs did not affect zinc cytotoxicity. In conclusion, we show that MT induction and zinc administration are novel strategies to sensitize colorectal cancer cells to presently utilized chemotherapeutic agents. Mol Cancer Ther; 13(5); 1369-81. Ó2014 AACR.

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“…We, along with others, have shown that CXCL8 signalling contributes to the transition of a disease to a castration-resistant state (Araki et al, 2007;Seaton et al, 2008). Furthermore, we have shown that CXC-chemokine signalling (including CXCL8) modulates the sensitivity of CaP cells to environmental stresses such as hypoxia and chemotherapy agents, including the DNA-damage agents oxaliplatin and etoposide Wilson et al, 2008a).…”

mentioning

confidence: 95%

“…RNA was harvested and prepared for analysis by quantitative realtime (qPCR) as previously described (Wilson et al, 2008a). The cDNA (50 ng) was mixed with primers (2 nM), sterile water and SYBR Green PCR mastermix (Finnzymes Diagnostics, Espoo, Finland).…”

Section: Quantitative Real-time Pcrmentioning

confidence: 99%

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Inhibition of constitutive and cxc-chemokine-induced NF-κB activity potentiates ansamycin-based HSP90-inhibitor cytotoxicity in castrate-resistant prostate cancer cells

Seaton¹,

Maxwell²,

Hill³

et al. 2009

Br J Cancer

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BACKGROUND: We determined how CXC-chemokine signalling and necrosis factor-kB (NF-kB) activity affected heat-shock protein 90 (Hsp90) inhibitor (geldanamycin (GA) and 17-allylamino-demethoxygeldanamycin (17-AAG)) cytotoxicity in castrate-resistant prostate cancer (CRPC). METHODS: Geldanamycin and 17-AAG toxicity, together with the CXCR2 antagonist AZ10397767 or NF-kB inhibitor BAY11-7082, was assessed by 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay in two CRPC lines, DU145 and PC3. Flow cytometry quantified apoptotic or necrosis profiles. Necrosis factor-kB activity was determined by luciferase readouts or indirectly by quantitative PCR and ELISA-based determination of CXCL8 expression. RESULTS: Geldanamycin and 17-AAG reduced PC3 and DU145 cell viability, although PC3 cells were less sensitive. Addition of AZ10397767 increased GA (e.g., PC3 IC 20 : from 1.67 ± 0.4 to 0.18 ± 0.2 nM) and 17-AAG (PC3 IC 20 : 43.7 ± 7.8 to 0.64 ± 1.8 nM) potency in PC3 but not DU145 cells. Similarly, BAY11-7082 increased the potency of 17-AAG in PC3 but not in DU145 cells, correlating with the elevated constitutive NF-kB activity in PC3 cells. AZ10397767 increased 17-AAG-induced apoptosis and necrosis and decreased NF-kB activity/CXCL8 expression in 17-AAG-treated PC3 cells. CONCLUSION: Ansamycin cytotoxicity is enhanced by inhibiting NF-kB activity and/or CXC-chemokine signalling in CRPC cells. Detecting and/or inhibiting NF-kB activity may aid the selection and treatment response of CRPC patients to Hsp90 inhibitors.

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Chemotherapy-Induced CXC-Chemokine/CXC-Chemokine Receptor Signaling in Metastatic Prostate Cancer Cells Confers Resistance to Oxaliplatin through Potentiation of Nuclear Factor-κB Transcription and Evasion of Apoptosis

Cited by 101 publications

References 33 publications

Dexamethasone potentiates the antiangiogenic activity of docetaxel in castration-resistant prostate cancer

Dexamethasone potentiates the antiangiogenic activity of docetaxel in castration-resistant prostate cancer

Metallothionein 1G and Zinc Sensitize Human Colorectal Cancer Cells to Chemotherapy

Inhibition of constitutive and cxc-chemokine-induced NF-κB activity potentiates ansamycin-based HSP90-inhibitor cytotoxicity in castrate-resistant prostate cancer cells

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