Novel peptides suppress VEGFR-3 activity and antagonize VEGFR-3-mediated oncogenic effects

Chang, Yi Wen; Su, Chih-Ming; Su, Yea-Huey; Ho, Yuan Soon; Lai, Hui Huang; Chen, Hsin An; Kuo, Min Liang; Hung, Wen Chun; Lin, Chen‐Yong; Wu, Chih Hsiung; Chen, Pai Sheng; Su, Jen Liang

doi:10.18632/oncotarget.1709

Cited by 31 publications

(23 citation statements)

References 33 publications

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“…VE GF-A a nd -C a re m a j or re gul a t ors of lymphangiogenesis [ 36 , 37 ]. In order to unveil the mechanism by which Cav-1 regulates PCa lymphangiogenic potential, we measured the effect of modulating Cav-1 expression on the production of VEGF-A and VEGF-C in PCa cell-conditioned media using ELISA.…”

Section: Resultsmentioning

confidence: 99%

Non-caveolar caveolin-1 expression in prostate cancer cells promotes lymphangiogenesis

et al. 2015

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Lymphangiogenesis allows prostate cancer (PCa) lymphatic metastasis, which is associated with poor prognosis and short survival rates. Caveolin-1 (Cav-1) is a membrane protein localized in caveolae, but also exists in non-caveolar, cellular or extracellular forms. Cav-1 is overexpressed in PCa, promotes prostate tumour progression and metastasis. We investigated the effect of caveolar and non-caveolar Cav-1 on PCa lymphangiogenic potential. Cav-1 was down-regulated in PC3 and DU145, and ectopically expressed in LNCaP cells. The effect of PCa cell conditioned media on lymphatic endothelial cell (LEC) viability, chemotaxis, chemokinesis and differentiation was assessed. The effect of Cav-1 on PCa cell expression of lymphangiogenesis-modulators VEGF-A and VEGF-C was assessed using qPCR and ELISA of the conditioned medium. Non-caveolar Cav-1, whether exogenous or endogenous (in LNCaP and PC3 cells, respectively) enhanced LEC proliferation, migration and differentiation. In contrast, caveolar Cav-1 (in DU145 cells) did not significantly affect PCa cell lymphangiogenic potential. The effect of non-caveolar Cav-1 on LECs was mediated by increased expression of VEGF-A as demonstrated by neutralization by anti-VEGF-A antibody. This study unveils for the first time a crucial role for non-caveolar Cav-1 in modulating PCa cell expression of VEGF-A and subsequent LEC proliferation, migration and tube formation.

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Section: Resultsmentioning

confidence: 99%

Non-caveolar caveolin-1 expression in prostate cancer cells promotes lymphangiogenesis

et al. 2015

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“…We further identify VEGF-C/VEGFR3-mediated YAP1 and Slug expression through KRAS/MAPK signaling in skin cancer. By treating skin cancer cells with an anti-VEGFR3 specific peptide [ 26 ], we show that suppression of VEGF-C/VEGFR3 signaling significantly reduces YAP1 and Slug expression and diminishes the migration, invasion and cancer stemness of the cells. In conclusion, our findings provide a novel signaling pathway, the VEGF-C/VEGFR3-KRAS/MAPK-YAP1/Slug axis, in skin cancer progression and a potential therapeutic strategy by treatment with an anti-VEGFR3 peptide.…”

Section: Introductionmentioning

confidence: 99%

Targeting the VEGF-C/VEGFR3 axis suppresses Slug-mediated cancer metastasis and stemness via inhibition of KRAS/YAP1 signaling

et al. 2016

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Vascular endothelial growth factor-C (VEGF-C) has been implicated in epithelial-mesenchymal transition (EMT) processes and various human cancers, including skin cancer. Skin cancer is an aggressive human malignancy with increasing incidence worldwide; however, the underlying mechanisms involved in VEGF-C-induced skin cancer stemness and metastasis remain unclear. Here, we report that VEGF-C enhances skin cancer migration, invasion and stemness through Slug up-regulation. Oncomine database analysis indicated that the KRAS/MAPK (mitogen-activated protein kinases) pathway and YAP1 (yes-associated protein 1) expression are positively correlated with metastatic skin cancer. We show that VEGF-C triggers the activation of KRAS/MAPK signaling to increase YAP1 and downstream Slug expression, which are suppressed by an anti-VEGFR3 (VEGF receptor 3) peptide, a specific peptide targeting VEGFR3. The VEGF-C-induced migration, invasion and stemness of skin cancer cells are also abrogated by the anti-VEGFR3 peptide. Based on these data, we reveal the role of the VEGF-C/VEGFR3-mediated KRAS/MAPK-YAP1/Slug pathway in skin cancer progression and propose that the VEGF-C/VEGFR3 axis is a promising target for the anti-VEGFR3 peptide.

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“…VEGF-C-induced VEGFR3 activity has been linked to cancer metastasis and disease progression in lung cancer patients [149]. Peptides developed to inhibit the kinase activity of VEGFR3 suppress VEGF-C-mediated cancer cell invasiveness and VEGF-C-induced drug resistance by inhibiting VEGFR3-linked signal transduction [149]. In addition to anti-angiogenic agents, it is desirable that pro-angiogenic drugs will be developed as high impact therapies for cardiovascular diseases.…”

Section: Drugs and Diseasementioning

confidence: 99%

The cellular response to vascular endothelial growth factors requires co-ordinated signal transduction, trafficking and proteolysis

et al. 2015

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SynopsisVEGFs (vascular endothelial growth factors) are a family of conserved disulfide-linked soluble secretory glycoproteins found in higher eukaryotes. VEGFs mediate a wide range of responses in different tissues including metabolic homoeostasis, cell proliferation, migration and tubulogenesis. Such responses are initiated by VEGF binding to soluble and membrane-bound VEGFRs (VEGF receptor tyrosine kinases) and co-receptors. VEGF and receptor splice isoform diversity further enhances complexity of membrane protein assembly and function in signal transduction pathways that control multiple cellular responses. Different signal transduction pathways are simultaneously activated by VEGFR-VEGF complexes with membrane trafficking along the endosome-lysosome network further modulating signal output from multiple enzymatic events associated with such pathways. Balancing VEGFR-VEGF signal transduction with trafficking and proteolysis is essential in controlling the intensity and duration of different intracellular signalling events. Dysfunction in VEGF-regulated signal transduction is important in chronic disease states including cancer, atherosclerosis and blindness. This family of growth factors and receptors is an important model system for understanding human disease pathology and developing new therapeutics for treating such ailments.

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Novel peptides suppress VEGFR-3 activity and antagonize VEGFR-3-mediated oncogenic effects

Cited by 31 publications

References 33 publications

Non-caveolar caveolin-1 expression in prostate cancer cells promotes lymphangiogenesis

Non-caveolar caveolin-1 expression in prostate cancer cells promotes lymphangiogenesis

Targeting the VEGF-C/VEGFR3 axis suppresses Slug-mediated cancer metastasis and stemness via inhibition of KRAS/YAP1 signaling

The cellular response to vascular endothelial growth factors requires co-ordinated signal transduction, trafficking and proteolysis

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