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| Content Provider | PubMed Central |
|---|---|
| Author | Schultz, David J. Wickramasinghe, Nalinie S. Ivanova, Margarita M. Isaacs, Susan M. Dougherty, Susan M. Imbert-fernandez, Yoannis Cunningham, Albert R. Chen, Chunyuan Klinge, Carolyn M. |
| Abstract | Anacardic acid (2-hydroxy-6-alkylbenzoic acid) is a dietary and medicinal phytochemical with established anticancer activity in cell and animal models. The mechanisms by which anacardic acid inhibits cancer cell proliferation remain undefined. Anacardic acid 24:1ω5 (AnAc 24:1ω5) was purified from geranium (Pelargonium × hortorum) and shown to inhibit the proliferation of estrogen receptor α (ERα)-positive MCF-7 and endocrine-resistant LCC9 and LY2 breast cancer cells with greater efficacy than ERα-negative primary human breast epithelial cells, MCF-10A normal breast epithelial cells, and MDA-MB-231 basal-like breast cancer cells. AnAc 24:1ω5 inhibited cell cycle progression and induced apoptosis in a cell-specific manner. AnAc 24:1ω5 inhibited estradiol (E2)-induced estrogen response element (ERE) reporter activity and transcription of the endogenous E2-target genes: pS2, cyclin D1, and cathepsin D in MCF-7 cells. AnAc 24:1ω5 did not compete with E2 for ERα or ERβ binding, nor did AnAc 24:1ω5 reduce ERα or ERβ steady state protein levels in MCF-7 cells; rather, AnAc 24:1ω5 inhibited ER-ERE binding in vitro. Virtual Screening with the molecular docking software Surflex evaluated AnAc 24:1ω5 interaction with ERα ligand binding and DNA binding domains (LBD and DBD) in conjunction with experimental validation. Molecular modeling revealed AnAc 24:1ω5 interaction with the ERα DBD but not the LBD. Chromatin immunoprecipitation (ChIP) experiments revealed that AnAc 24:1ω5 inhibited E2-ERα interaction with the endogenous pS2 gene promoter region containing an ERE. These data indicate that AnAc 24:1ω5 inhibits cell proliferation, cell cycle progression and apoptosis in an ER-dependent manner by reducing ER-DNA interaction and inhibiting ER-mediated transcriptional responses. |
| Related Links | http://dx.doi.org/10.1158/1535-7163.MCT-09-0978 |
| Starting Page | 594 |
| File Format | |
| ISSN | 15388514 |
| e-ISSN | 15388514 |
| Journal | Molecular cancer therapeutics |
| Issue Number | 3 |
| Volume Number | 9 |
| Language | English |
| Publisher Date | 2010-03-01 |
| Access Restriction | Open |
| Subject Keyword | Research in Higher Education |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cancer Research Oncology |
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