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Guggulsterone inhibits angiogenesis by blocking STAT3 and VEGF expression in colon cancer cells

Authors
 EUN SOO KIM  ;  SUNG YI HONG  ;  HYE KYUNG LEE  ;  SEUNG WON KIM  ;  MIN JI AN  ;  TAE IL KIM  ;  KYOUNG RYUL LEE  ;  WON HO KIM  ;  JAE HEE CHEON 
Citation
 ONCOLOGY REPORTS, Vol.20(6) : 1321-1327, 2008 
Journal Title
ONCOLOGY REPORTS
ISSN
 1021-335X 
Issue Date
2008
MeSH
Angiogenesis Inhibitors/pharmacology ; Cell Line, Tumor ; Cell Movement ; Colonic Neoplasms/drug therapy ; Colonic Neoplasms/metabolism* ; Endothelium, Vascular/metabolism ; Gene Expression Regulation, Neoplastic* ; Humans ; Models, Biological ; Neoplasm Metastasis ; Neovascularization, Pathologic* ; Pregnenediones/pharmacology* ; Promoter Regions, Genetic ; STAT3 Transcription Factor/metabolism* ; Tetrazolium Salts/pharmacology ; Thiazoles/pharmacology ; Vascular Endothelial Growth Factor A/metabolism*
Keywords
Angiogenesis Inhibitors/pharmacology ; Cell Line, Tumor ; Cell Movement ; Colonic Neoplasms/drug therapy ; Colonic Neoplasms/metabolism* ; Endothelium, Vascular/metabolism ; Gene Expression Regulation, Neoplastic* ; Humans ; Models, Biological ; Neoplasm Metastasis ; Neovascularization, Pathologic* ; Pregnenediones/pharmacology* ; Promoter Regions, Genetic ; STAT3 Transcription Factor/metabolism* ; Tetrazolium Salts/pharmacology ; Thiazoles/pharmacology ; Vascular Endothelial Growth Factor A/metabolism*
Abstract
The plant sterol guggulsterone has been shown to exert anti-tumor effects, making it a candidate chemotherapeutic agent. We investigated the anti-tumor effects of guggulsterone on colon cancer cells and elucidated the underlying molecular mechanisms related to angiogenesis. The apoptotic effects of guggulsterone were examined by cell survival assay. Western blot analysis was used to determine the levels of various down-stream intracellular proteins involved in angiogenesis, including signal transducer and activator of transcription 3 (STAT3), vascular endothelial growth factor (VEGF), hypoxia-inducible factor-1alpha (HIF-1alpha) and aryl hydrocarbon receptor nuclear translocator (ARNT). Using chromatin immunoprecipitation assay, we tested whether guggulsterone affects the recruitment of STAT3, ARNT and HIF-1alpha to the human VEGF promoter. To investigate the effect of guggulsterone on vascular endothelial cell migration and invasion, tube formation and migration assays were conducted using human umbilical vein endothelial cells (HUVECs). Matrix metalloproteinase (MMP)-2 and -9 activities were measured by gelatin zymography. Guggulsterone significantly reduced cell viability in colon cancer cells in a dose-dependent manner and blocked VEGF, ARNT and STAT3 expression prominently in hypoxic conditions. The recruitment of STAT3 and ARNT, but not HIF-1alpha, to the VEGF promoter was inhibited by guggulsterone treatment. HUVECs produced much foreshortened and severely broken tubes and showed decreased migration activity under guggulsterone effects. In addition, zymography revealed that MMP-2 and -9 enzyme activities were markedly lower in the presence of guggulsterone. The results of this study suggest that guggulsterone not only induces apoptosis, but also inhibits angiogenesis and metastasis in colon cancer cells by blocking STAT3 and VEGF expression, suggesting its therapeutic potential in the treatment of colorectal cancer.
Full Text
http://www.spandidos-publications.com/or/20/6/1321
DOI
10.3892/or_00000147
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Others (기타) > 1. Journal Papers
Yonsei Authors
Kim, Seung Won(김승원) ORCID logo https://orcid.org/0000-0002-1692-1192
Kim, Won Ho(김원호) ORCID logo https://orcid.org/0000-0002-5682-9972
Kim, Eun Soo(김은수)
Kim, Tae Il(김태일) ORCID logo https://orcid.org/0000-0003-4807-890X
Cheon, Jae Hee(천재희) ORCID logo https://orcid.org/0000-0002-2282-8904
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/107788
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