p130Cas/Cyclooxygenase-2 axis in the control of mesenchymal plasticity of breast cancer cells

Bisarò, Brigitte; Montani, Maura; Konstantinidou, Georgia; Marchini, Cristina; Pietrella, Lucia; Iezzi, Manuela; Galiè, Mirco; Orso, Francesca; Camporeale, Annalisa; Colombo, Shana; Stefano, Paola Di; Tornillo, Giusy; Camacho-Leal, M.P.; Turco, Emilia; Taverna, Daniela; Cabodi, Sara; Amici, Augusto; Defilippi, Paola

doi:10.1186/bcr3342

Cited by 25 publications

(17 citation statements)

References 43 publications

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“…7d, middle panel). As previous studies demonstrated that the activation of p130Cas is associated with the induction of the mesenchymal markers Slug and N-cadherin (33,34), the levels of these markers were .01 vs. the respective control IgG-treated cells. cMet, tyrosine-protein kinase Met; TGFβ-R, transforming growth factor β receptor; FGF-R, fibroblast growth factor receptor; PdGF-R, platelet-derived growth factor receptor; dMSO, dimethylsulfoxide; HGF, hepatocyte growth factor; IgG, immunoglobulin G; Ab, antibody; HCT/ctl, control HCT116 cells; RKO/ctl, control RKO cells; HCT/suni, sunitinib-adapted HCT116 cells; RKO/suni, sunitinib-adapted RKO cells; HPF, high power field.…”

Section: Nrp1-dependent Cmet Activation In the Sunitinib-adapted Cellmentioning

confidence: 64%

VEGF pathway-targeting drugs induce evasive adaptation by activation of neuropilin-1/cMet in colon cancer cells

et al. 2018

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Anti-angiogenic therapies targeting vascular endothelial growth factor (VEGF) and its receptor (VEGF-R) are important treatments for a number of human malignancies, including colorectal cancers. However, there is increasing evidence that VEGF/VEGF-R inhibitors promote the adaptive and evasive resistance of tumor cells to the therapies. The mechanism by which the cancer cells become resistant remains unclear. One potential mechanism is that VEGF/VEGF-R blockers directly act on tumor cells independently of anti-angiogenic effects. In this study, the direct effects of an anti-VEGF antibody (bevacizumab) and a VEGF-R tyrosine kinase inhibitor (sunitinib) on the evasive adaptation of colon cancer cells were compared. HCT116 and RKO human colon cancer cell lines were chronically exposed (3 months) to bevacizumab or sunitinib in vitro to establish bevacizumab- and sunitinib-adapted cells, respectively. Transwell migration and invasion assays, western blotting, reverse transcription-quantitative polymerase chain reaction, co-immunoprecipitation analysis, cell survival assays and ELISAs were conducted to analyze the adapted cells. Compared with the control vehicle-treated cells, the two cell models exhibited increased migration and invasion activities to different degrees and through different mechanisms. The bevacizumab-adapted cells, but not in the sunitinib-adapted cells, exhibited redundantly increased expression levels of VEGF/VEGF-R family members, including VEGF-A, placental growth factor, VEGF-C, VEGF-R1 and VEGF-R3. In addition, the phosphorylation levels of VEGF-R1 and VEGF-R3 were increased in the bevacizumab-adapted cells compared with the control cells. Thus, the inhibition of VEGF-R1 and VEGF-R3 decreased the evasive activities of the cells, suggesting that they remained dependent on redundant VEGF/VEGF-R signaling. By contrast, the sunitinib-adapted cells exhibited increased neuropilin-1 (NRP1) expression levels compared with the control cells. In the sunitinib-adapted cells, NRP1 interacted with phosphorylated cMet, and the cMet activation was dependent on NRP1. Thus, NRP1 or cMet blockade suppressed the evasive activation of the sunitinib-adapted cells. These results suggest that the sunitinib-adapted cells switched from a VEGF-R-dependent pathway to an alternative NRP1/cMet-dependent one. The findings of the present study indicate that VEGF/VEGF-R inhibitors directly act on colon cancer cells and activate their evasive adaptation via different mechanisms.

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Section: Nrp1-dependent Cmet Activation In the Sunitinib-adapted Cellmentioning

confidence: 64%

VEGF pathway-targeting drugs induce evasive adaptation by activation of neuropilin-1/cMet in colon cancer cells

et al. 2018

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“…P130cas (BCAR1) was downregulated in whole flaxseed supplemented diet while AP1 transcription factor family member, MAFF was downregulated in whole flaxseed, defatted flax meal and flax oil diets. P130cas is an adhesion protein that is upregulated in breast cancer [66], promotes cell migration and induces tamoxifen resistance [67]. E2 exposure leads to upregulation of Maf transcription factors in breast cancer [68] and promotes distant metastasis [69].…”

Section: Discussionmentioning

confidence: 99%

Flaxseed and its components differentially affect estrogen targets in pre-neoplastic hen ovaries

Dikshit

Gao

Small

et al. 2016

The Journal of Steroid Biochemistry and Molecular Biology

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Flaxseed has been studied for decades for its health benefits that include anti-cancer, cardioprotective, anti-diabetic, anti-inflammatory properties. The biologically active components that mediate these effects are the omega-3 fatty acids and the lignan, secoisolaricirescinol diglucoside. We have previously shown that whole flaxseed supplemented diet decreases the severity and incidence of ovarian cancer while a 15% dose of flaxseed is most protective against inflammation and estrogen-induced chemical and genotoxicity. The objective of this study was to dissect the independent effects of the two flaxseed components on estrogen signaling and metabolism. Two and half year old hens were fed either a control diet, 15% whole flaxseed diet, defatted flax meal diet or 5% flax oil diet for 3 months after which the animals were sacrificed and blood and tissues were harvested. Whole flaxseed diet caused a decrease in expression of ERα. ERα target gene expression was assessed using RT2 profiler PCR array. Some targets involved in the IGF/insulin signaling pathway (IRS1, IGFBP4, IGFBP5) were downregulated by flaxseed and its components. Flaxseed diet also downregulated AKT expression. A number of targets related to NF-κB signaling were altered by flaxseed diet including a series of targets implicated in cancer. Whole flaxseed diet also affected E2 metabolism by increasing CYP1A1 expression with a corresponding increase in the onco-protective E2 metabolite, 2-methoxyestradiol. The weak anti-estrogens, enterolactone, enterodiol and 2-methoxyestradiol, might be working synergistically to generate a protective effect on the ovaries from hens on whole flaxseed diet by altering the estrogen signaling and metabolism.

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“…Thus, deregulation of Pyk2 and, perhaps, paxillin likely played a role in the altered migration of PTPN12-deficient breast cancer cells. Although it remains to be clarified if Pyk2 and paxillin or, possibly, Cas played a role in the increased resistance to anoikis and EMT caused by PTPN12 deficiency, it is noteworthy that previous work showed that Cas has a role in EMT (36,37).…”

Section: Discussionmentioning

confidence: 99%

Loss of PTPN12 Stimulates Progression of ErbB2-Dependent Breast Cancer by Enhancing Cell Survival, Migration, and Epithelial-to-Mesenchymal Transition

Davidson

Souza

et al. 2015

Molecular and Cellular Biology

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e PTPN12 is a cytoplasmic protein tyrosine phosphatase (PTP) reported to be a tumor suppressor in breast cancer, through its capacity to dephosphorylate oncogenic receptor protein tyrosine kinases (PTKs), such as ErbB2. However, the precise molecular and cellular impact of PTPN12 deficiency in breast cancer progression remains to be fully clarified. Here, we addressed this issue by examining the effect of PTPN12 deficiency on breast cancer progression in vivo, in a mouse model of ErbB2-dependent breast cancer using a conditional PTPN12-deficient mouse. Our studies showed that lack of PTPN12 in breast epithelial cells accelerated breast cancer development and lung metastases in vivo. PTPN12-deficient breast cancer cells displayed enhanced tyrosine phosphorylation of the adaptor Cas, the adaptor paxillin, and the kinase Pyk2. They exhibited no detectable increase in ErbB2 tyrosine phosphorylation. PTPN12-deficient cells were more resistant to anoikis and had augmented migratory and invasive properties. Enhanced migration was corrected by inhibiting Pyk2. PTPN12-deficient breast cancer cells also acquired partial features of epithelial-to-mesenchymal transition (EMT), a feature of more aggressive forms of breast cancer. Hence, loss of PTPN12 promoted tumor progression in a mouse model of breast cancer, supporting the notion that PTPN12 is a tumor suppressor in human breast cancer. This function was related to the ability of PTPN12 to suppress cell survival, migration, invasiveness, and EMT and to inhibit tyrosine phosphorylation of Cas, Pyk2, and paxillin. These findings enhance our understanding of the role and mechanism of action of PTPN12 in the control of breast cancer progression. P rotein tyrosine phosphatases (PTPs) play a key role in normal cellular processes, such as proliferation, migration, adhesion, differentiation, and immune cell activation (1-3). Depending on the phosphatase and the cell type, they also have the ability either to suppress or to promote malignant transformation (3). PTPN12, also referred to as PTP-PEST (PTP-proline, glutamic acid, serine, and threonine rich), is a cytoplasmic PTP expressed in a wide spectrum of cell types (4). Studies of PTPN12-deficient mice showed that PTPN12 is a critical positive regulator of migration and adhesion in embryonic fibroblasts, endothelial cells, T cells, macrophages, and dendritic cells (5-11). This function relates to the capacity of PTPN12 to dephosphorylate cytoskeletonassociated substrates such as protein tyrosine kinases (PTKs) Pyk2 and FAK or the adaptors Cas, paxillin, and PSTPIP-1. These substrates are components of the cellular machinery controlling migration and adhesion. PTPN12 can also regulate other substrates, including receptor PTKs, such as ErbB2 and the adaptor . Proteomic data suggested that the ability of PTPN12 to regulate Shc might be critical for conversion of Shc-dependent proliferative signals into migratory signals (15). Several PTPN12 substrates, and in particular, Cas, paxillin, and Shc, also directly associate with PTPN12....

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p130Cas/Cyclooxygenase-2 axis in the control of mesenchymal plasticity of breast cancer cells

Cited by 25 publications

References 43 publications

VEGF pathway-targeting drugs induce evasive adaptation by activation of neuropilin-1/cMet in colon cancer cells

VEGF pathway-targeting drugs induce evasive adaptation by activation of neuropilin-1/cMet in colon cancer cells

Flaxseed and its components differentially affect estrogen targets in pre-neoplastic hen ovaries

Loss of PTPN12 Stimulates Progression of ErbB2-Dependent Breast Cancer by Enhancing Cell Survival, Migration, and Epithelial-to-Mesenchymal Transition

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