CAPE suppresses VEGFR-2 activation, and tumor neovascularization and growth

Tae Wook Chung, Seok Jo Kim, Hee Jung Choi, Choong Hwan Kwak, Kwon Ho Song, Seok Jong Suh, Keuk Jun Kim, Ki Tae Ha, Young Guk Park, Young Chae Chang, Hyeun Wook Chang, Young Choon Lee, Cheorl Ho Kim*

*Corresponding author for this work

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

The growth and metastasis of human solid tumors and the development of conditions such as diabetic retinopathy, rheumatoid arthritis, inflammatory psoriasis, and others are regulated by the balance between angiogenic stimulators and inhibitors released in the angiogenic-pathological microenvironment. Vascular endothelial growth factor (VEGF), an angiogenic factor, is a potent endothelial-specific mitogen that activates endothelial cells in pathological angiogenesis. Recently, we demonstrated that caffeic acid phenethyl ester (CAPE) inhibits tumor growth, invasion, and metastasis. However, the precise molecular mechanism underlying the inhibitory effect of CAPE on VEGF-mediated angiogenesis remains unknown. Here, we show that CAPE suppressed VEGF-induced proliferation, tube formation, migration, the formation of actin stress fibers and loss of VE-cadherin at cell-cell contacts in endothelial cells, indicating the inhibition of VEGF-mediated VEGF receptor-2 (VEGFR-2) and its downstream signal activation in vitro. CAPE blocked VEGF-stimulated neovascularization in the Matrigel plugs assay, and reduced vascular permeability in mouse skin capillaries in vivo. CAPE inhibited the growth and neovascularization of primary tumor cells in C57BL/6 and BALB/c mice inoculated with Lewis lung carcinoma, colon carcinoma, and melanoma cells. These results suggest that CAPE negatively modulates VEGF-induced angiogenesis by suppressing VEGFR-2 activation, and might be a therapeutic avenue for anti-angiogenesis.

Original languageEnglish (US)
Pages (from-to)271-282
Number of pages12
JournalJournal of Molecular Medicine
Volume91
Issue number2
DOIs
StatePublished - Feb 1 2013

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Vascular Endothelial Growth Factor Receptor
Vascular Endothelial Growth Factor A
Growth
Neoplasms
Endothelial Cells
Pathologic Neovascularization
Neoplasm Metastasis
Lewis Lung Carcinoma
Vascular Endothelial Growth Factor Receptor-2
Stress Fibers
Angiogenesis Inhibitors
Angiogenesis Inducing Agents
Capillary Permeability
Diabetic Retinopathy
Mitogens
Psoriasis
caffeic acid phenethyl ester
Actins
Melanoma
Rheumatoid Arthritis

Keywords

  • Angiogenesis
  • Caffeic acid phenethyl ester (CAPE)
  • Vascular endothelial growth factor (VEGF)
  • Vascular endothelial growth factor receptor-2 (VEGFR-2)

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)

Cite this

Chung, T. W., Kim, S. J., Choi, H. J., Kwak, C. H., Song, K. H., Suh, S. J., ... Kim, C. H. (2013). CAPE suppresses VEGFR-2 activation, and tumor neovascularization and growth. Journal of Molecular Medicine, 91(2), 271-282. https://doi.org/10.1007/s00109-012-0952-6
Chung, Tae Wook ; Kim, Seok Jo ; Choi, Hee Jung ; Kwak, Choong Hwan ; Song, Kwon Ho ; Suh, Seok Jong ; Kim, Keuk Jun ; Ha, Ki Tae ; Park, Young Guk ; Chang, Young Chae ; Chang, Hyeun Wook ; Lee, Young Choon ; Kim, Cheorl Ho. / CAPE suppresses VEGFR-2 activation, and tumor neovascularization and growth. In: Journal of Molecular Medicine. 2013 ; Vol. 91, No. 2. pp. 271-282.
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Chung, TW, Kim, SJ, Choi, HJ, Kwak, CH, Song, KH, Suh, SJ, Kim, KJ, Ha, KT, Park, YG, Chang, YC, Chang, HW, Lee, YC & Kim, CH 2013, 'CAPE suppresses VEGFR-2 activation, and tumor neovascularization and growth', Journal of Molecular Medicine, vol. 91, no. 2, pp. 271-282. https://doi.org/10.1007/s00109-012-0952-6

CAPE suppresses VEGFR-2 activation, and tumor neovascularization and growth. / Chung, Tae Wook; Kim, Seok Jo; Choi, Hee Jung; Kwak, Choong Hwan; Song, Kwon Ho; Suh, Seok Jong; Kim, Keuk Jun; Ha, Ki Tae; Park, Young Guk; Chang, Young Chae; Chang, Hyeun Wook; Lee, Young Choon; Kim, Cheorl Ho.

In: Journal of Molecular Medicine, Vol. 91, No. 2, 01.02.2013, p. 271-282.

Research output: Contribution to journalArticle

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T1 - CAPE suppresses VEGFR-2 activation, and tumor neovascularization and growth

AU - Chung, Tae Wook

AU - Kim, Seok Jo

AU - Choi, Hee Jung

AU - Kwak, Choong Hwan

AU - Song, Kwon Ho

AU - Suh, Seok Jong

AU - Kim, Keuk Jun

AU - Ha, Ki Tae

AU - Park, Young Guk

AU - Chang, Young Chae

AU - Chang, Hyeun Wook

AU - Lee, Young Choon

AU - Kim, Cheorl Ho

PY - 2013/2/1

Y1 - 2013/2/1

N2 - The growth and metastasis of human solid tumors and the development of conditions such as diabetic retinopathy, rheumatoid arthritis, inflammatory psoriasis, and others are regulated by the balance between angiogenic stimulators and inhibitors released in the angiogenic-pathological microenvironment. Vascular endothelial growth factor (VEGF), an angiogenic factor, is a potent endothelial-specific mitogen that activates endothelial cells in pathological angiogenesis. Recently, we demonstrated that caffeic acid phenethyl ester (CAPE) inhibits tumor growth, invasion, and metastasis. However, the precise molecular mechanism underlying the inhibitory effect of CAPE on VEGF-mediated angiogenesis remains unknown. Here, we show that CAPE suppressed VEGF-induced proliferation, tube formation, migration, the formation of actin stress fibers and loss of VE-cadherin at cell-cell contacts in endothelial cells, indicating the inhibition of VEGF-mediated VEGF receptor-2 (VEGFR-2) and its downstream signal activation in vitro. CAPE blocked VEGF-stimulated neovascularization in the Matrigel plugs assay, and reduced vascular permeability in mouse skin capillaries in vivo. CAPE inhibited the growth and neovascularization of primary tumor cells in C57BL/6 and BALB/c mice inoculated with Lewis lung carcinoma, colon carcinoma, and melanoma cells. These results suggest that CAPE negatively modulates VEGF-induced angiogenesis by suppressing VEGFR-2 activation, and might be a therapeutic avenue for anti-angiogenesis.

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KW - Angiogenesis

KW - Caffeic acid phenethyl ester (CAPE)

KW - Vascular endothelial growth factor (VEGF)

KW - Vascular endothelial growth factor receptor-2 (VEGFR-2)

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