| PRO-APOPTOTIC PROTEIN, SMAC, MEDIATES APOPTOSIS IN CISPLATIN-RESISTANT OVARIAN CANCER CELLS WHEN TREATED WITH THE ANTI-TUMOR AGENT, AT101. | |
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MedLine Citation:
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PMID: 22052903 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Chemoresistance of ovarian cancer has been associated previously to the expression and activation of Bcl-2 family proteins. BH3-mimetic molecules possessing potential anticancer utility are able to inhibit the activity of antiapoptotic Bcl-2 family proteins. AT101 (R-(-)-gossypol), a natural BH3-mimetic molecule, has shown anti-tumor activity in a variety of tumor models as a single agent and in combination with standard anticancer therapies. Here we reported the effect of AT101 on apoptosis in cisplatin-resistant ovarian cancer cells and identified the major molecular event that determines sensitivity. Our data indicated that AT101 induced cell apoptosis by activating Bax conformational change, translocation and oligomerization. The inhibition of Bax expression only partially prevented caspase-3 cleavage. However, surprisingly, the gene silencing of Bax had no effect on mitochondrial Smac release. Further experiments demonstrated that Smac reduction inhibited caspase-3 activation and attenuated cell apoptosis. More importantly, the inhibition of Smac or overexpression of XIAP attenuated Bax activation in ovarian cells. Furthermore, our data indicate that the Akt-p53 pathway is involved in the regulation of Smac release. Taken together, we demonstrated the roles of Smac and the molecular mechanisms in AT101-induced apoptosis of chemoresistant ovarian cancer cells. Our findings suggest that AT101 not only triggers Bax activation but also induces mitochondrial Smac release. Activated Smac can enhance Bax-mediated cellular apoptosis. Therefore, Smac mediates Bax activation to determine the threshold for overcoming cisplatin resistance in ovarian cancer cells. |
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Authors:
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Wenbin Hu; Fang Wang; Jingsheng Tang; Xinyu Liu; Zhu Yuan; Chunlai Nie; Yuquan Wei |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-11-3 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: - ISSN: 1083-351X ISO Abbreviation: - Publication Date: 2011 Nov |
Date Detail:
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Created Date: 2011-11-4 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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State Key Laboratory of Biotherapy and Cancer Center, West China Hospital,Sichuan University, China; |
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