TRAIL negatively regulates VEGF-induced angiogenesis via caspase-8-mediated enzymatic and non-enzymatic functions

Hee Jun Na, Jong Yun Hwang, Kwang Soon Lee, Yoon Kyung Choi, Jongseon Choe, Ji Yoon Kim, Hyo Eun Moon, Kyu Won Kim, Gou Young Koh, Hansoo Lee, Dooil Jeoung, Moo Ho Won, Kwon Soo Ha, Young-Guen Kwon, Young Myeong Kim

Research output: Contribution to journalArticle

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Abstract

Solid tumors supply oxygen and nutrients required for angiogenesis by producing vascular endothelial growth factor (VEGF). Thus, inhibitors of VEGF signaling abrogate tumor angiogenesis, resulting in the suppression of tumor growth and metastasis. We here investigated the effects of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on VEGF-induced angiogenesis. TRAIL inhibited VEGF-induced in vitro angiogenesis of human umbilical vein endothelial cells (HUVECs) and in vivo neovascularization in chicken embryos and mice. TRAIL blocked VEGF-induced angiogenic signaling by inhibiting ERK, Src, FAK, paxillin, Akt, and eNOS. Further, TRAIL blocked intracellular Ca 2+ elevation and actin reorganization in HUVECs stimulated with VEGF, without inhibiting VEGF receptor-2 tyrosine phosphorylation. TRAIL increased caspase-8 activity, without inducing caspase-9/-3 activation and apoptosis. Moreover, TRAIL resulted in cleavage of FAK into FAK-related non-kinase-like fragments in VEGF-stimulated HUVECs, which was blocked by a caspase-8 inhibitor and cellular caspase-8-like inhibitory protein. Biochemical and pharmacological inhibition of caspase-8 and FAK blocked the inhibitory effects of TRAIL on VEGF-stimulated anti-angiogenic signaling and events. In addition, caspase-8 knockdown also suppressed VEGF-mediated signaling and angiogenesis, suggesting that procaspase-8 plays a role of a non-apoptotic modulator in VEGF-induced angiogenic signaling. These results suggest that TRAIL inhibits VEGF-induced angiogenesis by increasing caspase-8 activity and subsequently decreasing non-apoptotic signaling functions of procaspase-8, without inducing caspase-3 activation and endothelial cell cytotoxicity. These data indicate that caspase-8 may be used as an anti-angiogenic drug for solid tumors resistant to TRAIL and anti-tumor drugs.

Original languageEnglish
Pages (from-to)179-194
Number of pages16
JournalAngiogenesis
Volume17
Issue number1
DOIs
Publication statusPublished - 2014 Jan 1

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Caspase 8
Vascular Endothelial Growth Factor A
Endothelial cells
Tumors
Human Umbilical Vein Endothelial Cells
Neoplasms
Caspase 3
Chemical activation
Apoptosis
Paxillin
Oxygen supply
Vascular Endothelial Growth Factor Receptor-2
Phosphorylation
Caspase Inhibitors
Angiogenesis Inhibitors
Caspase 9
Cytotoxicity
Modulators
Nutrients
Actins

All Science Journal Classification (ASJC) codes

  • Physiology
  • Clinical Biochemistry
  • Cancer Research

Cite this

Na, H. J., Hwang, J. Y., Lee, K. S., Choi, Y. K., Choe, J., Kim, J. Y., ... Kim, Y. M. (2014). TRAIL negatively regulates VEGF-induced angiogenesis via caspase-8-mediated enzymatic and non-enzymatic functions. Angiogenesis, 17(1), 179-194. https://doi.org/10.1007/s10456-013-9387-0
Na, Hee Jun ; Hwang, Jong Yun ; Lee, Kwang Soon ; Choi, Yoon Kyung ; Choe, Jongseon ; Kim, Ji Yoon ; Moon, Hyo Eun ; Kim, Kyu Won ; Koh, Gou Young ; Lee, Hansoo ; Jeoung, Dooil ; Won, Moo Ho ; Ha, Kwon Soo ; Kwon, Young-Guen ; Kim, Young Myeong. / TRAIL negatively regulates VEGF-induced angiogenesis via caspase-8-mediated enzymatic and non-enzymatic functions. In: Angiogenesis. 2014 ; Vol. 17, No. 1. pp. 179-194.
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abstract = "Solid tumors supply oxygen and nutrients required for angiogenesis by producing vascular endothelial growth factor (VEGF). Thus, inhibitors of VEGF signaling abrogate tumor angiogenesis, resulting in the suppression of tumor growth and metastasis. We here investigated the effects of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on VEGF-induced angiogenesis. TRAIL inhibited VEGF-induced in vitro angiogenesis of human umbilical vein endothelial cells (HUVECs) and in vivo neovascularization in chicken embryos and mice. TRAIL blocked VEGF-induced angiogenic signaling by inhibiting ERK, Src, FAK, paxillin, Akt, and eNOS. Further, TRAIL blocked intracellular Ca 2+ elevation and actin reorganization in HUVECs stimulated with VEGF, without inhibiting VEGF receptor-2 tyrosine phosphorylation. TRAIL increased caspase-8 activity, without inducing caspase-9/-3 activation and apoptosis. Moreover, TRAIL resulted in cleavage of FAK into FAK-related non-kinase-like fragments in VEGF-stimulated HUVECs, which was blocked by a caspase-8 inhibitor and cellular caspase-8-like inhibitory protein. Biochemical and pharmacological inhibition of caspase-8 and FAK blocked the inhibitory effects of TRAIL on VEGF-stimulated anti-angiogenic signaling and events. In addition, caspase-8 knockdown also suppressed VEGF-mediated signaling and angiogenesis, suggesting that procaspase-8 plays a role of a non-apoptotic modulator in VEGF-induced angiogenic signaling. These results suggest that TRAIL inhibits VEGF-induced angiogenesis by increasing caspase-8 activity and subsequently decreasing non-apoptotic signaling functions of procaspase-8, without inducing caspase-3 activation and endothelial cell cytotoxicity. These data indicate that caspase-8 may be used as an anti-angiogenic drug for solid tumors resistant to TRAIL and anti-tumor drugs.",
author = "Na, {Hee Jun} and Hwang, {Jong Yun} and Lee, {Kwang Soon} and Choi, {Yoon Kyung} and Jongseon Choe and Kim, {Ji Yoon} and Moon, {Hyo Eun} and Kim, {Kyu Won} and Koh, {Gou Young} and Hansoo Lee and Dooil Jeoung and Won, {Moo Ho} and Ha, {Kwon Soo} and Young-Guen Kwon and Kim, {Young Myeong}",
year = "2014",
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Na, HJ, Hwang, JY, Lee, KS, Choi, YK, Choe, J, Kim, JY, Moon, HE, Kim, KW, Koh, GY, Lee, H, Jeoung, D, Won, MH, Ha, KS, Kwon, Y-G & Kim, YM 2014, 'TRAIL negatively regulates VEGF-induced angiogenesis via caspase-8-mediated enzymatic and non-enzymatic functions', Angiogenesis, vol. 17, no. 1, pp. 179-194. https://doi.org/10.1007/s10456-013-9387-0

TRAIL negatively regulates VEGF-induced angiogenesis via caspase-8-mediated enzymatic and non-enzymatic functions. / Na, Hee Jun; Hwang, Jong Yun; Lee, Kwang Soon; Choi, Yoon Kyung; Choe, Jongseon; Kim, Ji Yoon; Moon, Hyo Eun; Kim, Kyu Won; Koh, Gou Young; Lee, Hansoo; Jeoung, Dooil; Won, Moo Ho; Ha, Kwon Soo; Kwon, Young-Guen; Kim, Young Myeong.

In: Angiogenesis, Vol. 17, No. 1, 01.01.2014, p. 179-194.

Research output: Contribution to journalArticle

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T1 - TRAIL negatively regulates VEGF-induced angiogenesis via caspase-8-mediated enzymatic and non-enzymatic functions

AU - Na, Hee Jun

AU - Hwang, Jong Yun

AU - Lee, Kwang Soon

AU - Choi, Yoon Kyung

AU - Choe, Jongseon

AU - Kim, Ji Yoon

AU - Moon, Hyo Eun

AU - Kim, Kyu Won

AU - Koh, Gou Young

AU - Lee, Hansoo

AU - Jeoung, Dooil

AU - Won, Moo Ho

AU - Ha, Kwon Soo

AU - Kwon, Young-Guen

AU - Kim, Young Myeong

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Solid tumors supply oxygen and nutrients required for angiogenesis by producing vascular endothelial growth factor (VEGF). Thus, inhibitors of VEGF signaling abrogate tumor angiogenesis, resulting in the suppression of tumor growth and metastasis. We here investigated the effects of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on VEGF-induced angiogenesis. TRAIL inhibited VEGF-induced in vitro angiogenesis of human umbilical vein endothelial cells (HUVECs) and in vivo neovascularization in chicken embryos and mice. TRAIL blocked VEGF-induced angiogenic signaling by inhibiting ERK, Src, FAK, paxillin, Akt, and eNOS. Further, TRAIL blocked intracellular Ca 2+ elevation and actin reorganization in HUVECs stimulated with VEGF, without inhibiting VEGF receptor-2 tyrosine phosphorylation. TRAIL increased caspase-8 activity, without inducing caspase-9/-3 activation and apoptosis. Moreover, TRAIL resulted in cleavage of FAK into FAK-related non-kinase-like fragments in VEGF-stimulated HUVECs, which was blocked by a caspase-8 inhibitor and cellular caspase-8-like inhibitory protein. Biochemical and pharmacological inhibition of caspase-8 and FAK blocked the inhibitory effects of TRAIL on VEGF-stimulated anti-angiogenic signaling and events. In addition, caspase-8 knockdown also suppressed VEGF-mediated signaling and angiogenesis, suggesting that procaspase-8 plays a role of a non-apoptotic modulator in VEGF-induced angiogenic signaling. These results suggest that TRAIL inhibits VEGF-induced angiogenesis by increasing caspase-8 activity and subsequently decreasing non-apoptotic signaling functions of procaspase-8, without inducing caspase-3 activation and endothelial cell cytotoxicity. These data indicate that caspase-8 may be used as an anti-angiogenic drug for solid tumors resistant to TRAIL and anti-tumor drugs.

AB - Solid tumors supply oxygen and nutrients required for angiogenesis by producing vascular endothelial growth factor (VEGF). Thus, inhibitors of VEGF signaling abrogate tumor angiogenesis, resulting in the suppression of tumor growth and metastasis. We here investigated the effects of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on VEGF-induced angiogenesis. TRAIL inhibited VEGF-induced in vitro angiogenesis of human umbilical vein endothelial cells (HUVECs) and in vivo neovascularization in chicken embryos and mice. TRAIL blocked VEGF-induced angiogenic signaling by inhibiting ERK, Src, FAK, paxillin, Akt, and eNOS. Further, TRAIL blocked intracellular Ca 2+ elevation and actin reorganization in HUVECs stimulated with VEGF, without inhibiting VEGF receptor-2 tyrosine phosphorylation. TRAIL increased caspase-8 activity, without inducing caspase-9/-3 activation and apoptosis. Moreover, TRAIL resulted in cleavage of FAK into FAK-related non-kinase-like fragments in VEGF-stimulated HUVECs, which was blocked by a caspase-8 inhibitor and cellular caspase-8-like inhibitory protein. Biochemical and pharmacological inhibition of caspase-8 and FAK blocked the inhibitory effects of TRAIL on VEGF-stimulated anti-angiogenic signaling and events. In addition, caspase-8 knockdown also suppressed VEGF-mediated signaling and angiogenesis, suggesting that procaspase-8 plays a role of a non-apoptotic modulator in VEGF-induced angiogenic signaling. These results suggest that TRAIL inhibits VEGF-induced angiogenesis by increasing caspase-8 activity and subsequently decreasing non-apoptotic signaling functions of procaspase-8, without inducing caspase-3 activation and endothelial cell cytotoxicity. These data indicate that caspase-8 may be used as an anti-angiogenic drug for solid tumors resistant to TRAIL and anti-tumor drugs.

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