Growth inhibition and differentiation of human breast cancer cells by the PAFR antagonist WEB-2086

Cellai, Cristina; Laurenzana, Anna; Vannucchi, Alessandro M.; Caporale, Roberto; Paglierani, Milena; Lollo, Simonetta Di; Pancrazzi, Alessandro; Paoletti, Francesco

doi:10.1038/sj.bjc.6603156

Cited by 31 publications

(27 citation statements)

References 24 publications

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“…These findings were consistent with molecular biology results showing that WEB-2170 caused the downmodulation of several genes linked to cell proliferation and antiapoptotic pathways, while other genes promoting cell growth arrest, as well as the extrinsic and intrinsic apoptosis, were significantly upregulated. Apparently, the process was independent of p53 [26] and histone acetylation [13]. Moreover, we proved that WEB-2170 acts as an inverse agonist rather than an antagonist of PAF-r; this way, the drug induces the functional inactivation of PAF-r accompanied by a decrease in IP levels and this might be a critical metabolic event dictating the downstream inhibition of the PI3K/AKT signaling pathway.…”

Section: Discussionmentioning

confidence: 82%

Mechanistic insight into WEB-2170-induced apoptosis in human acute myelogenous leukemia cells: The crucial role of PTEN

Cellai

Laurenzana

Bianchi

et al. 2009

Experimental Hematology

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Objective. This study aimed to investigate the mechanisms of action of WEB-2170, an inverse agonist of platelet-activating factor receptor, capable of inducing apoptosis in human acute myelogenous leukemia (AML) cells. Material and Methods. Gene expression profiling followed by cytofluorimetric, morphologic, and biologic analyses were used to monitor WEB-2170 effects in AML cell lines (ie, NB4, KG1, NB4-MR4, THP1, and U937) and blasts from patients with different AML (M0LM5) subtypes. PTEN silencing with small interfering RNA was also performed. Results. We have demonstrated that drug-mediated cytostasis/apoptosis in NB4 cells is characterized by upregulation of cyclin G2, p21/WAF1, NIX, TNFLa, and PTEN expression, and downregulation of cyclin D2 and BCL2 expression. We observed an increase in PTEN protein accompanied by a decrease in phospho-extracellular signal-regulated kinase 2 (ERK2) and phospho-AKT, and by forkhead box O3a (FOXO3a) cytoplasmic-nuclear translocation; the mitochondrial cytochrome C release and PARP cleavage marked the late apoptotic steps. We have found that WEB-2170 triggered apoptosis in NB4, KG1, and NB4-MR4 cells where PTEN was expressed, but not in THP1 and U937 cells where PTEN was absent. Finally, we show that PTEN silencing in NB4 cells by PTEN-specific small interfering RNA resulted in a significant reduction of drug-induced apoptosis. Conclusion. We demonstrated that WEB-2170 is a powerful antileukemic agent with interesting translational opportunities to treat AML and described mechanisms of drug-induced intrinsic and extrinsic apoptosis both in AML cell lines and blasts from AML patients by addressing PTEN as the master regulator of the whole process. Ó 2009 ISEH -Society for Hematology and Stem Cells. Published by Elsevier Inc.Acute promyelocytic leukemia (APL) with t(15;17) chromosomal translocation is a subtype of acute myelogeneous leukemia (AML) that can be successfully cured by alltrans-retinoic acid (ATRA) targeted therapy toward the PML/RARa fusion protein [1]. ATRA can also be used in combination with other agents to treat elderly AML patients carrying the nucleophosmin-1 mutation [2]. This approach, however, is not effective on ATRA-resistant APL forms and other AML (non-APL) subtypes [3], which are refractory to ATRA-induced differentiation [4]. Therefore, the current treatment for the bulk of the other AML subtypes still consists of high-dose chemotherapy with potential lifethreatening toxicity and acquired drug resistance [5].Inhibitors of histone deacetylases [6] and DNA demethylating agents [7,8] 2009;37:1176-1185 [9], thus providing additional tools for cancer therapy [10]. Indeed, epigenetic modulators are functional to set up an environment permissive for cell differentiation and/or apoptosis, but may not always be sufficient themselves to trigger these processes without the cooperation of other proactive signals. It is of great interest, therefore, to identify and characterize new agents capable of inducing cytostasis, differentiation, and apoptosis in AML...

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Section: Discussionmentioning

confidence: 82%

Mechanistic insight into WEB-2170-induced apoptosis in human acute myelogenous leukemia cells: The crucial role of PTEN

Cellai

Laurenzana

Bianchi

et al. 2009

Experimental Hematology

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“…This effect was more pronounced in MDA-MB231 tumors as compared to tumors derived from non-metastatic cells [87]. Moreover, PAFR antagonist WEB-2086 induces growth inhibition and differentiation of human breast cancer cells [93], while the PAFR antagonist BN-50730 inhibited human prostatic carcinoma xenografts in nude mice [27]. Bocceline et al have found that PAF acts as a potent inducer of tumor cell motility in CHO cells in vitro [94].…”

Section: The Role Of Paf In Various Cancersmentioning

confidence: 96%

Inflammation and melanoma growth and metastasis: The role of platelet-activating factor (PAF) and its receptor

Melnikova

Bar‐Eli

2007

Cancer Metastasis Rev

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An inflammatory tumor microenvironment fosters tumor growth, angiogenesis and metastatic progression. Platelet-activating factor (PAF) is an inflammatory biolipid produced from membrane glycerophospholipids. Through the activity of its G-protein coupled receptor, PAF triggers a variety of pathological reactions including tumor neo-angiogenesis. Several groups have demonstrated that inhibiting PAF-PAF receptor pathway at the level of a ligand or receptor results in an effective inhibition of experimental tumor growth and metastasis. In particular, our group has recently demonstrated that PAF receptor antagonists can effectively inhibit the metastatic potential of human melanoma cells in nude mice. Furthermore, we showed that PAF stimulated the phosphorylation of CREB and ATF-1 in metastatic melanoma cells, which resulted in overexpression of MMP-2 and MT1-MMP. Our data indicate that PAF acts as a promoter of melanoma metastasis in vivo. Since only metastatic melanoma cells overexpress CREB/ATF-1, we propose that these cells are better equipped to respond to PAF within the tumor microenvironment when compared to their non-metastatic counterparts.

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“…For example, the activation of PAFR can stimulate various kinases and the downstream signaling pathway to promote melanoma metastasis (7). Inhibition of PAFR activity by its specific inhibitor can effectively block the breast cancer cell growth and invasion in vitro (8). Disruption of the PAF/PAFR interaction or knockdown of the expression of PAFR can effectively block the invasion of ovarian tumor cells (9).…”

Section: Introductionmentioning

confidence: 99%

Feed-Forward Reciprocal Activation of PAFR and STAT3 Regulates Epithelial–Mesenchymal Transition in Non–Small Cell Lung Cancer

et al. 2015

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Platelet-activating factor receptor (PAFR), a G-protein-coupled receptor, has been implicated in tumorigenesis, but its contributions to metastatic progression have not been investigated. Here, we show that PAFR is overexpressed in non-small cell lung cancer (NSCLC) as well as in breast, colorectal, and gastric carcinomas. Expression of PAFR correlates closely with clinical stages, survival time, and distant metastasis. In human NSCLC cells, activation of the PAF/PAFR signaling axis accentuated malignant character, including by stimulating epithelial-mesenchymal transition (EMT). In contrast, silencing PAFR in aggressive NSCLC cells inhibited these effects. Mechanistic investigations showed that PAFR stimulated EMT by activating STAT3 via upregulation of G-protein-dependent SRC or JAK2 kinase activity. Notably, STAT3 transcriptionally elevated PAFR expression. Thus, activation of PAFR in NSCLC cells initiated a forward feedback loop responsible for mediating the aggressive malignant character of NSCLC cells in vitro and in vivo. Reinforcing this reciprocal activation loop, PAF/PAFR signaling also upregulated IL6 expression and thereby STAT3 activation. Overall, our results elucidated an important role for PAFR dysregulation in the pathogenicity of NSCLC and unraveled a forward feedback loop between PAFR and STAT3 that acts to drive the malignant progression of NSCLC. Cancer Res; 75(19); 4198-210. Ó2015 AACR.

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Growth inhibition and differentiation of human breast cancer cells by the PAFR antagonist WEB-2086

Cited by 31 publications

References 24 publications

Mechanistic insight into WEB-2170-induced apoptosis in human acute myelogenous leukemia cells: The crucial role of PTEN

Mechanistic insight into WEB-2170-induced apoptosis in human acute myelogenous leukemia cells: The crucial role of PTEN

Inflammation and melanoma growth and metastasis: The role of platelet-activating factor (PAF) and its receptor

Feed-Forward Reciprocal Activation of PAFR and STAT3 Regulates Epithelial–Mesenchymal Transition in Non–Small Cell Lung Cancer

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