title: Targeting beta-catenin signaling to induce apoptosis in human breast cancer cells by z-guggulsterone and Gugulipid extract of Ayurvedic medicine plant Commiphora mukul.
abstract: BACKGROUND
  z-Guggulsterone (z-Gug) and Gugulipid (GL) have been used to treat a variety of ailments. We now report their anti-cancer effect and mechanism against human breast cancer.
  
  
  METHODS
  Using the human estrogen receptor-positive (MCF-7) and triple-negative (MDA-MB-231) breast cancer cells as well as the normal human mammary epithelial cell line (HMEC), we evaluated the anti-breast-cancer efficacy and apoptosis inducing activity of GL. We determined the cellular and molecular mechanism of GL-inhibited breast cancer cell growth.
  
  
  RESULTS
  GL significantly inhibited growth of MCF-7 and MDA-MB-231 cells with an IC50~2 μM at pharmacologically relevant concentrations standardized to its major active constituent z-Gug. The GL-induced growth inhibition correlated with apoptosis induction as evidenced by an increase in cytoplasmic histone-associated DNA fragmentation and caspase 3 activity. The GL-induced apoptosis was associated with down-regulation of the β-Catenin signaling pathway. The decreased expression of Wnt/β-Catenin targeting genes, such as cyclin D1, C-myc and survivin, and the inhibition of the activity of the transcription factor (T-cell factor 4, TCF-4) were observed in GL-treated breast cancer cells. The GL treatment resulted in a significant reduction of β-Catenin /TCF-4 complex in both of the cancer cells. The GL-induced apoptotic cell death was significantly enhanced by RNA Interference of β-Catenin and TCF-4. On the other hand, the normal human mammary epithelial cell HMEC, compared with the human breast cancer cells, is significantly more resistant to growth inhibition and apoptosis induction by GL.
  
  
  CONCLUSIONS
  The present study indicates that the β-Catenin signaling pathway is the target for GL-induced growth inhibition and apoptosis in human breast cancer.
authors.affiliation: Department of General Surgery, The 2nd Affiliated Hospital of Soochow University, Suzhou 215004, Jiangsu, China. xs52308@hotmail.com
authors.forename: Guoqin
authors.initials: G
authors.lastname: Jiang
authors.forename: Xiao
authors.initials: X
authors.lastname: Xiao
authors.forename: Yan
authors.initials: Y
authors.lastname: Zeng
authors.forename: Kalyanam
authors.initials: K
authors.lastname: Nagabhushanam
authors.forename: Muhammed
authors.initials: M
authors.lastname: Majeed
authors.forename: Dong
authors.initials: D
authors.lastname: Xiao
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D029744:Commiphora / Q000737:chemistry*; D006801:Humans; D008515:Medicine, Ayurvedic; D010936:Plant Extracts / Q000494:pharmacology*; D053149:Plant Gums / Q000494:pharmacology*; D011282:Pregnenediones / Q000494:pharmacology*; D011485:Protein Binding; D015398:Signal Transduction / Q000187:drug effects; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D010936:Plant Extracts; D053149:Plant Gums; D011282:Pregnenediones; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D051176:beta Catenin; C018562:guggulu extract; C023617:pregna-4,17-diene-3,16-dione
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