Tyrosine kinase inhibitors as antiproliferative agents against an estrogen-dependent breast cancer cell line in vitro

Twaddle, George M.; Turbov, Jane M.; Liu, Naxin; Murthy, Satya

doi:10.1002/(sici)1096-9098(199902)70:2<83::aid-jso4>3.0.co;2-l

Cited by 20 publications

(11 citation statements)

References 25 publications

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“…These evidences suggest that exosome-derived RTKs could be the activators of Ras. RTKs are a major type of cell surface receptor, and family members, such as EGFR, HER2, and InR, are expressed on the plasma membrane of cancer cells (43). We found that phosphorylated forms of HER2 and EGFR were present in MCF-7-derived exosomes (Fig.…”

Section: Discussionmentioning

confidence: 73%

Cancer Cell-derived Exosomes Induce Mitogen-activated Protein Kinase-dependent Monocyte Survival by Transport of Functional Receptor Tyrosine Kinases

Song

Ding

Liu

et al. 2016

Journal of Biological Chemistry

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Tumor-associated macrophages (TAM) play pivotal roles in cancer initiation and progression. Monocytes, the precursors of TAMs, normally undergo spontaneous apoptosis within 2 days, but can subsist in the inflammatory tumor microenvironment for continuous survival and generation of sufficient TAMs. The mechanisms underlying tumor-driving monocyte survival remain obscure. Here we report that cancer cell-derived exosomes were crucial mediators for monocyte survival in the inflammatory niche. Analysis of the survival-promoting molecules in monocytes revealed that cancer cell-derived exosomes activated Ras and extracellular signalregulated kinases in the mitogen-activated protein kinase (MAPK) pathway, resulting in the prevention of caspase cleavage. Phosphorylated receptor tyrosine kinases (RTKs), such as phosphorylated epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER-2), were abundantly expressed in cancer cell-derived exosomes. Knock-out of EGFR or/and HER-2, or alternatively, inhibitors against their phosphorylation significantly disturbed the exosome-mediated activation of the MAPK pathway, inhibition of caspase cleavage, and increase in survival rate in monocytes. Moreover, the deprived survival-stimulating activity of exosomes due to null expression of EGFR and HER-2 could be restored by activation of another RTK, insulin receptor. Overall, our study uncovered a mechanism of tumor-associated monocyte survival and demonstrated that cancer cell-derived exosomes can stimulate the MAPK pathway in monocytes through transport of functional RTKs, leading to inactivation of apoptosis-related caspases. This work provides insights into the long sought question on monocyte survival prior to formation of plentiful TAMs in the tumor microenvironment.Clinical and experimental evidences suggest that a particular type of macrophage population is present within the tumor microenvironment (1). Tumor-associated macrophages (TAMs) 4 are derived from recruited monocytes or resident tissue macrophages (2), and play essential roles in tumor initiation, progression, and metastasis (3). Monocyte recruitment, survival, and differentiation are fundamental steps for continuous generation of TAMs. Previous studies are focused on understanding the complicated mechanisms of monocyte recruitment and differentiation within tumor tissues (2). However, investigations regarding how monocytes maintain survival before differentiation into sufficient TAMs have never been reported.As key components of the innate immune system, monocytes are continuously produced by bone marrow but normally undergo spontaneous apoptosis within 48 h in blood circulation (4, 5). Monocyte apoptosis can be prevented in vitro by serum at high concentrations (Ͼ20%), differentiation factors, and a wide range of inflammatory stimuli such as lipopolysaccharide (LPS) and interferon-␥ (IFN-␥), all of which reduce the activation of caspases and trigger the differentiation of monocytes into macrophages or dendritic cells (5-10). However, i...

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Section: Discussionmentioning

confidence: 73%

Cancer Cell-derived Exosomes Induce Mitogen-activated Protein Kinase-dependent Monocyte Survival by Transport of Functional Receptor Tyrosine Kinases

Song

Ding

Liu

et al. 2016

Journal of Biological Chemistry

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“…This enhancement of phosphorylation was abolished by a PDGFR-specific kinase inhibitor, tyrphostin (AG1295), which has been used to specifically abrogate the activation of PDGFR (39)(40)(41)(42). Tyrphostin has shown promising results for the treatment of proliferative vitreoretinopathy, aortic allograft vasculopathy, and restenosis.…”

Section: Discussionmentioning

confidence: 99%

Platelet-Derived Growth Factor Receptor β–Mediated Phosphorylation of MUC1 Enhances Invasiveness in Pancreatic Adenocarcinoma Cells

Singh

Wen

Swanson³

et al. 2007

Cancer Research

104

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MUC1 is a heterodimeric transmembrane glycoprotein that is overexpressed and aberrantly glycosylated in ductal adenocarcinomas. Differential phosphorylation of the MUC1 cytoplasmic tail (MUC1CT) has been associated with signaling events that influence the proliferation and metastasis of cancer cells. We identified a novel tyrosine phosphorylation site (HGRYVPP) in the MUC1CT by mass spectrometric analysis of MUC1 from human pancreatic adenocarcinoma cell lines. Analyses in vitro and in vivo showed that plateletderived growth factor receptor B (PDGFRB) catalyzed phosphorylation of this site and of tyrosine in the RDTYHPM site. Stimulation of S2-013.MUC1F cells with PDGF-BB increased nuclear colocalization of MUC1CT and B-catenin. PDGF-BB stimulation had no significant effect on cell proliferation rate; however, it enhanced invasion in vitro through Matrigel and in vivo tumor growth and metastases. Invasive properties of the cells were significantly altered on expression of phosphorylation-abrogating or phosphorylation-mimicking mutations at these sites. We propose that interactions of MUC1 and PDGFRB induce signal transduction events that influence the metastatic properties of pancreatic adenocarcinoma. [Cancer Res 2007;67(11):5201-10]

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“…31 In addition, we used tyrphostin AG99 to examine the effect of blocking ERK1/2, which is located downstream in the IGF-I signal transduction pathway. As tyrphostin AG99 is known to exert biological activities not only on ERK1 and ERK2 activity but also on EGF-R phosphorylation, 32 and although tyrphostin A1 (which we used as control), widely described to have no biological activity (only one recent study showed an influence on proliferative activity), 33 we additionally used U0126 and antisense technique to evaluate the effect of blocking ERK1/2 translation on apoptosis of HSC and rMF.…”

Section: Influence Of Igf-i Receptor Phosphorylation Blockage and Erkmentioning

confidence: 99%

IGF-I induces DNA synthesis and apoptosis in rat liver hepatic stellate cells (HSC) but DNA synthesis and proliferation in rat liver myofibroblasts (rMF)

Saile

DiRocco

Dudás

et al. 2004

Laboratory Investigation

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Several lines of evidence suggest a role of insulin-like growth factor I (IGF-I) in the regulation of apoptosis. Up to now its impact on many specific cells is unknown. We therefore studied the effect of IGF-I on two similar mesenchymal matrix-producing cell types of the liver, the hepatic stellate cells (HSC) and the myofibroblasts (rMF). The present study aimed to reveal the influence of IGF-I on cell cycle and apoptosis of HSC and rMF and to elucidate responsible signaling. While IGF-I significantly increased DNA synthesis in HSC, cell number decreased and apoptosis increased. In rMF IGF-I also increased DNA synthesis, which is, however, followed by proliferation. Blocking extracellular signal regulating kinase (ERK) revealed that in HSC, bcl-2 upregulation and bax downregulation are effected downstream of ERK, whereas downregulation of NFjB and consecutive of bclx L is mediated upstream. In the rMF upregulation of both, the antiapoptotic bcl-2 and bcl-x L is mediated upstream of ERK. The expression of the proapoptotic bax is not regulated by IGF-I in rMF. The studies demonstrate a completely different effect and signaling of IGF-I in two morphologically and functionally similar matrix-producing cells of the liver.

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Tyrosine kinase inhibitors as antiproliferative agents against an estrogen-dependent breast cancer cell line in vitro

Cited by 20 publications

References 25 publications

Cancer Cell-derived Exosomes Induce Mitogen-activated Protein Kinase-dependent Monocyte Survival by Transport of Functional Receptor Tyrosine Kinases

Cancer Cell-derived Exosomes Induce Mitogen-activated Protein Kinase-dependent Monocyte Survival by Transport of Functional Receptor Tyrosine Kinases

Platelet-Derived Growth Factor Receptor β–Mediated Phosphorylation of MUC1 Enhances Invasiveness in Pancreatic Adenocarcinoma Cells

IGF-I induces DNA synthesis and apoptosis in rat liver hepatic stellate cells (HSC) but DNA synthesis and proliferation in rat liver myofibroblasts (rMF)

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