EPOX inhibits angiogenesis by degradation of Mcl-1 through ERK inactivation

Hui Lung Sun, An Chi Tsai, Shiow Lin Pan, Qingqing Ding, Hirohito Yamaguchi, Chun Nan Lin, Mien Chie Hung, Che Ming Teng

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Abstract

Purpose: Antiangiogenic therapy is considered as an effective strategy for controlling the growth and metastasis of tumors. Among a myriad of biological activities described for xanthone derivatives, the anticancer activity is quite remarkable, but the molecular mechanism is not clearly resolved. In the present study, we investigated the antiangiogenic mechanism of 3,6-di(2,3-epoxypropoxy) xanthone (EPOX), a novel Mcl-1 targeting drug. Experimental Design: To evaluate the antiangiogenic activity of EPOX, we did cell viability, cell cycle, tube formation assay in vitro, and Matrigel plug assay in vivo. To evaluate the effect of EPOX on the endothelial signaling pathway, we did immunoblotting, immunoprecipitation, and immunofluorescence analysis. Intracellular glutathione levels were determined with the use of monochlorobimane, a glutathione-specific probe. Results: EPOX induced endothelial cell apoptosis in association with proteasomedependent Mcl-1 degradation. Down-regulation of Mcl-1 resulted in an increase in Mcl-1-free Bim, activation of Bax, and then signaling of mitochondria-mediated apoptosis. Additionally, glutathione depletion and extracellular signal-regulated kinase (ERK) inactivation was observed in EPOX-treated cells. Glutathione supplementation reversed the inhibitory effects of EPOX on ERK, which increases the phosphorylation ofMcl-1 at T163. Overexpression of mitogen-activated protein/ERK kinase (MEK) partially reversed the effect of EPOX on Mcl-1 dephosphorylation, ubiquitination, and degradation, further implicating ERK in the regulation of Mcl-1 stability. Conclusions: This study provides evidence that EPOX induces glutathione depletion, ERK inactivation, and Mcl-1 degradation on endothelial cells, which leads to inhibition of angiogenesis. Our results suggest that EPOX is a novel antiangiogenic agent, making it a promising lead compound for further development in the treatment of angiogenesisrelated pathologies.

Original languageEnglish
Pages (from-to)4904-4914
Number of pages11
JournalClinical Cancer Research
Volume15
Issue number15
DOIs
Publication statusPublished - Aug 1 2009
Externally publishedYes

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Sun, H. L., Tsai, A. C., Pan, S. L., Ding, Q., Yamaguchi, H., Lin, C. N., Hung, M. C., & Teng, C. M. (2009). EPOX inhibits angiogenesis by degradation of Mcl-1 through ERK inactivation. Clinical Cancer Research, 15(15), 4904-4914. https://doi.org/10.1158/1078-0432.CCR-09-0269