Expression and Activity of Src Regulate Interleukin-8 Expression in Pancreatic Adenocarcinoma Cells: Implications for Angiogenesis

Treviño, José G.; Summy, Justin M.; Gray, Michael J.; Nilsson, Monique B.; Lesslie, Donald P.; Baker, Cheryl H.; Gallick, Gary E.

doi:10.1158/0008-5472.can-04-3858

Cited by 75 publications

(71 citation statements)

References 40 publications

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“…3B). By using an inhibitor of phospho-p38 (SB 203580) (26) (Fig. S6A), an increase in CBP/p300 expression is seen in NT-transduced cell lines, demonstrating that p38 inhibits CBP/p300 ( Fig.…”

Section: Par-1 Regulates Binding Of Ets-1 and C-jun To The Maspin Promentioning

confidence: 94%

Protease activated receptor-1 inhibits the Maspin tumor-suppressor gene to determine the melanoma metastatic phenotype

Villares

Zigler

Dobroff

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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The thrombin receptor protease activated receptor-1 (PAR-1) is overexpressed in metastatic melanoma cell lines and tumor specimens. Previously, we demonstrated a significant reduction in tumor growth and experimental lung metastasis after PAR-1 silencing via systemic delivery of siRNA encapsulated into nanoliposomes. Gene expression profiling identified a 40-fold increase in expression of Maspin in PAR-1-silenced metastatic melanoma cell lines. Maspin promoter activity was significantly increased after PAR-1 silencing, suggesting that PAR1 negatively regulates Maspin at the transcriptional level. ChIP analyses revealed that PAR-1 decreases binding of Ets-1 and c-Jun transcription factors to the Maspin promoter, both known to activate Maspin transcription. PAR-1 silencing did not affect Ets-1 or c-Jun expression; rather it resulted in increased expression of the chromatin remodeling complex CBP/p300, as well as decreased activity of the CBP/p300 inhibitor p38, resulting in increased binding of Ets-1 and c-Jun to the Maspin promoter and higher Maspin expression. Functionally, Maspin expression reduced the invasive capability of melanoma cells after PAR-1 silencing, which was abrogated after rescuing with PAR-1. Furthermore, tumor growth and experimental lung metastasis was significantly decreased after expressing Maspin in a metastatic melanoma cell line. Moreover, silencing Maspin in PAR-1-silenced cells reverted the inhibition of tumor growth and experimental lung metastasis. Herein, we demonstrate a mechanism by which PAR-1 negatively regulates the expression of the Maspin tumor-suppressor gene in the acquisition of the metastatic melanoma phenotype, thus attributing an alternative function to PAR-1 other than coagulation. melanoma progression | transcriptional regulation | G protein-coupled receptor signaling | Serpin B5

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Section: Par-1 Regulates Binding Of Ets-1 and C-jun To The Maspin Promentioning

confidence: 94%

Protease activated receptor-1 inhibits the Maspin tumor-suppressor gene to determine the melanoma metastatic phenotype

Villares

Zigler

Dobroff

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…siRNA expression plasmids were created as described elsewhere, 13 using the Ambion pSilencer 1.0-U6 (Austin, TX) according to manufacturer's directions. Briefly, c-Srcspecific target sequences were designed using the Ambion siRNA Web design tool.…”

Section: Creation Of Small Interfering Rna (Sirna) Expression Plasmidmentioning

confidence: 99%

“…We have recently demonstrated that Src is a critical regulator of pro-angiogenic molecules. [13][14][15] Duxbury et al 16 have provided evidence that gemcitabine resistance correlates with increased Src activity, and Src inhibition overcomes this resistance. Recently, Src inhibition with a novel Src family kinase inhibitor has demonstrated significant antitumor and antimetastatic activity in a pancreatic cancer orthotopic nude mouse model.…”

mentioning

confidence: 99%

Inhibition of Src Expression and Activity Inhibits Tumor Progression and Metastasis of Human Pancreatic Adenocarcinoma Cells in an Orthotopic Nude Mouse Model

Treviño

Summy

Lesslie

et al. 2006

The American Journal of Pathology

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178

121

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The nonreceptor protein tyrosine kinase Src is overexpressed in 70% of pancreatic adenocarcinomas. Here, we describe the effect of molecular and pharmacological down-regulation of Src on incidence, growth, and metastasis of pancreatic tumor cells in an orthotopic model. Src expression in L3.6pl human pancreatic tumor cells was reduced by stable expression of a plasmid encoding small interfering RNA (siRNA) to c-src. In stable siRNA clones, Src expression was reduced >80%, with no change in expression of the related kinases c-Yes and c-Lyn, and proliferation rates were similar in all clones. Phosphorylation of Akt and p44/42 Erk mitogen-activated protein kinase and production of VEGF and IL-8 in culture supernatants were also reduced (P < 0.005). On orthotopic implantation of varying cell numbers into nude mice, tumor incidence was unchanged; however, in the siRNA clones, large tumors failed to develop, and incidence of metastasis was significantly reduced, suggesting that c-Src activity is critical to tumor progression. To examine this possibility further, animals bearing established wild-type tumors were treated with the Src/Abl-selective inhibitor BMS-354825 (dasatinib). Tumor size was decreased, and incidence of metastases was significantly reduced in treated mice compared with controls. These results demonstrate that Src activation contributes to pancreatic tumor progression in this model, offering Src as a candidate for

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“…The role of proinflammatory cytokines in tumour progression, angiogenesis and metastases has been elucidated in recent years. Specifically, IL-8 was shown to be a potent proangiogenic factor associated with increased microvessel count, increased VEGF expression and poor prognosis in oesophageal squamous cell carcinoma, colonic cancer cells and pancreatic adenocarcinoma cells (Mizukami et al, 2005;Ren et al, 2005;Trevino et al, 2005). Various studies have shown that blocking IL-8 expression reversed many of these proangiogenic and metastatic cell activities, further supporting the important role of this proinflammatory cytokine in tumour progression ((Mizukami et al, 2005;Ren et al, 2005;Trevino et al, 2005).…”

mentioning

confidence: 96%

Moxifloxacin enhances antiproliferative and apoptotic effects of etoposide but inhibits its proinflammatory effects in THP-1 and Jurkat cells

et al. 2006

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Etoposide (VP-16) is a topoisomerase II (topo II) inhibitor chemotherapeutic agent. Studies indicate that VP-16 enhances proinflammatory cytokines secretion from tumour cells, including IL-8, a chemokine associated with proangiogenic effects. Fluoroquinolones inhibit topo II activity in eukaryotic cells by a mechanism different from that of VP-16. The fluoroquinolone moxifloxacin (MXF) has pronounced anti-inflammatory effects in vitro and in vivo. We studied the effects of MXF and VP-16 on purified human topo II activity and further analysed their combined activity on proliferation, apoptosis and caspase-3 activity in THP-1 and Jurkat cells. Moxifloxacin alone slightly inhibited the activity of human topo II; however, in combination with VP-16 it led to a 73% reduction in enzyme activity. VP-16 inhibited cell proliferation in a time and dose-dependent manner. The addition of moxifloxacin for 72 h to low-dose VP-16 doubled its cytotoxic effect in THP-1 and Jurkat cells (1.8-and 2.6-fold decrease in cell proliferation, respectively) (Po0.004). Moxifloxacin given alone did not induce apoptosis but enhanced VP-16-induced apoptosis in THP-1 and Jurkat cells (1.8-and two-fold increase in annexin V positive cells and caspase-3 activity, respectively) (Po0.04). VP-16 induced the release of IL-8 in a time and dose-dependent manner from THP-1 cells. Moxifloxacin completely blocked the enhanced release of IL-8 induced by 0.5 and 1 mg ml À1 VP-16, and decreased IL-8 release from cells incubated for 72 h with 3 mg ml À1 VP-16 (Po0.001). VP-16 enhanced the release of IL-1b and TNF-a from THP-1 cells, whereas the addition of MXF prevented the enhanced cytokine secretion (Po0.001). We conclude that MXF significantly enhances VP-16 cytotoxicity in tumour-derived cells while preventing VP-16-induced proinflammatory cytokine release. This unique combination may have clinical benefits and cytotoxic drug 'sparing effect' and should be further studied in vivo.

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Expression and Activity of Src Regulate Interleukin-8 Expression in Pancreatic Adenocarcinoma Cells: Implications for Angiogenesis

Cited by 75 publications

References 40 publications

Protease activated receptor-1 inhibits the Maspin tumor-suppressor gene to determine the melanoma metastatic phenotype

Protease activated receptor-1 inhibits the Maspin tumor-suppressor gene to determine the melanoma metastatic phenotype

Inhibition of Src Expression and Activity Inhibits Tumor Progression and Metastasis of Human Pancreatic Adenocarcinoma Cells in an Orthotopic Nude Mouse Model

Moxifloxacin enhances antiproliferative and apoptotic effects of etoposide but inhibits its proinflammatory effects in THP-1 and Jurkat cells

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