title: Proapoptotic protein Smac mediates apoptosis in cisplatin-resistant ovarian cancer cells when treated with the anti-tumor agent AT101.
abstract: Chemoresistance of ovarian cancer has been previously attributed to the expression and activation of Bcl-2 family proteins. BH3-mimetic molecules possessing potential anticancer activity are able to inhibit antiapoptotic Bcl-2 family proteins. AT101 (R-(-)-gossypol), a natural BH3-mimetic molecule, has shown anti-tumor activity as a single agent and in combination with standard anticancer therapies in a variety of tumor models. Here, we report the effect of AT101 on apoptosis in cisplatin-resistant ovarian cancer cells and identify the major molecular events that determine sensitivity. AT101 induced cell apoptosis by activating Bax through a conformational change, translocation, and oligomerization. The inhibition of Bax expression only partially prevented caspase-3 cleavage. However, 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, our data demonstrate the role of Smac and the molecular mechanisms of 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.
authors: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, 4 Keyuan Road, Hitech District, Chengdu 610041, China.
authors: Wenbin
authors: W
authors: Hu
authors: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, 4 Keyuan Road, Hitech District, Chengdu 610041, China.
authors: Fang
authors: F
authors: Wang
authors: ChongQing NewFine Biology Technology Co., Ltd., 8 Lingfang Road, Banqiao District, Chongqing 402460, China.
authors: Jingsheng
authors: J
authors: Tang
authors: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, 4 Keyuan Road, Hitech District, Chengdu 610041, China.
authors: Xinyu
authors: X
authors: Liu
authors: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, 4 Keyuan Road, Hitech District, Chengdu 610041, China.
authors: Zhu
authors: Z
authors: Yuan
authors: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, 4 Keyuan Road, Hitech District, Chengdu 610041, China. Electronic address: niecl1022@hotmail.com.
authors: Chunlai
authors: C
authors: Nie
authors: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, 4 Keyuan Road, Hitech District, Chengdu 610041, China.
authors: Yuquan
authors: Y
authors: Wei
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006072:Gossypol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D016159:Tumor Suppressor Protein p53; D051636:X-Linked Inhibitor of Apoptosis Protein; D051028:bcl-2-Associated X Protein; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3; D006072:Gossypol; D002945:Cisplatin; C028178:gossypol acetic acid