| Hispidulin sensitizes human ovarian cancer cells to TRAIL-induced apoptosis by AMPK activation leading to Mcl-1 block in translation. | |
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MedLine Citation:
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PMID: 20734985 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Whether hispidulin, a flavone from traditional Chinese medicine, can modulate the anticancer effects of the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), the cytokine currently in clinical trials was investigated. In the present study, we found that hispidulin potentiated the TRAIL-induced apoptosis in human ovarian cancer cells and converted TRAIL-resistant cells to TRAIL-sensitive cells. When examined for its mechanism, we found that hispidulin was highly effective in activation of caspases 8 and caspase 3 and consequent poly(ADP-ribose) polymerase (PARP) cleavage. Moreover, we found that hispidulin downregulated the expression of Mcl-1, Bcl-2, and Bcl-xL. Whereas the downregulation of Bcl-2 and Bcl-xL was less pronounced, the downregulation of Mcl-1 was quite dramatic and was time-dependent. This sensitization is controlled through the adenosine monophosphate (AMP)-activated protein kinase (AMPK), which is the central energy-sensing system of the cell. Interestingly, we determined that AMPK is activated upon hispidulin treatment, resulting in mammalian target of rapamycin (mTOR) inhibition leading to Mcl-1 decrease. Therefore, our results show a novel mechanism for the sensitization to TRAIL-induced apoptosis linking hispidulin treatment to Mcl-1 downexpression. In addition, this study provides a rationale for the combined use of death receptor (DR) ligands with AMPK activators or mTOR inhibitors in the treatment of human cancers. |
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Authors:
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Jung-Mu Yang; Chao-Ming Hung; Chen-Nan Fu; Jang-Chang Lee; Chi-Hung Huang; Muh-Hwa Yang; Chih-Li Lin; Jung-Yie Kao; Tzong-Der Way |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Journal of agricultural and food chemistry Volume: 58 ISSN: 1520-5118 ISO Abbreviation: J. Agric. Food Chem. Publication Date: 2010 Sep |
Date Detail:
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Created Date: 2010-09-15 Completed Date: 2011-01-14 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0374755 Medline TA: J Agric Food Chem Country: United States |
Other Details:
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Languages: eng Pagination: 10020-6 Citation Subset: IM |
Affiliation:
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Institute of Biochemistry, College of Life Science, National Chung Hsing University, Taichung, Taiwan. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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AMP-Activated Protein Kinases
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metabolism* Antineoplastic Agents / pharmacology Antineoplastic Agents, Phytogenic / pharmacology* Apoptosis / drug effects* Cell Line, Tumor Drug Synergism Enzyme Activation / drug effects Female Flavones / pharmacology* Humans Ovarian Neoplasms / drug therapy*, metabolism Proto-Oncogene Proteins c-bcl-2 / metabolism* TNF-Related Apoptosis-Inducing Ligand / pharmacology* |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/Antineoplastic Agents, Phytogenic; 0/Flavones; 0/Proto-Oncogene Proteins c-bcl-2; 0/TNF-Related Apoptosis-Inducing Ligand; 0/myeloid cell leukemia sequence 1 protein; 1447-88-7/hispidulin; EC 2.7.11.1/AMP-Activated Protein Kinases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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