title: Caspase-9 mediates Puma activation in UCN-01-induced apoptosis.
abstract: The protein kinase inhibitor 7-hydroxystaurosporine (UCN-01) is one of the most potent and frequently used proapoptotic stimuli. The BH3-only molecule of Bcl-2 family proteins has been reported to contribute to UCN-01-induced apoptosis. Here we have found that UCN-01 triggers Puma-induced mitochondrial apoptosis pathway. Our data confirmed that Akt-FoxO3a pathway mediated Puma activation. Importantly, we elucidate the detailed mechanisms of Puma-induced apoptosis. Our data have also demonstrated that caspase-9 is a decisive molecule of Puma induction after UCN-01 treatment. Caspase-9 mediates apoptosis through two kinds of feedback loops. On the one hand, caspase-9 enhances Puma activation by cleaving Bcl-2 and Bcl-xL independent of caspase-3. On the other hand, caspase-9 directly activated caspase-3 in the presence of caspase-3. Caspase-3 could cleave XIAP in an another positive feedback loop to further sensitize cancer cells to UCN-01-induced apoptosis. Therefore, caspase-9 mediates Puma activation to determine the threshold for overcoming chemoresistance in cancer cells.
authors.affiliation: The State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital and College of Life Science, Sichuan University, No. 17 People's South Road, Chengdu 610041, People's Republic of China.
authors.forename: C
authors.initials: C
authors.lastname: Nie
authors.affiliation: The State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital and College of Life Science, Sichuan University, No. 17 People's South Road, Chengdu 610041, People's Republic of China.
authors.forename: Y
authors.initials: Y
authors.lastname: Luo
authors.affiliation: The State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital and College of Life Science, Sichuan University, No. 17 People's South Road, Chengdu 610041, People's Republic of China.
authors.forename: X
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Nankai University School of Medicine/Collaborative Innovation Center of Biotherapy, Tianjin 300071, People's Republic of China.
authors.forename: N
authors.initials: N
authors.lastname: Luo
authors.affiliation: The State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital and College of Life Science, Sichuan University, No. 17 People's South Road, Chengdu 610041, People's Republic of China.
authors.forename: A
authors.initials: A
authors.lastname: Tong
authors.affiliation: The State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital and College of Life Science, Sichuan University, No. 17 People's South Road, Chengdu 610041, People's Republic of China.
authors.forename: X
authors.initials: X
authors.lastname: Liu
authors.affiliation: The State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital and College of Life Science, Sichuan University, No. 17 People's South Road, Chengdu 610041, People's Republic of China.
authors.forename: Z
authors.initials: Z
authors.lastname: Yuan
authors.affiliation: The State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital and College of Life Science, Sichuan University, No. 17 People's South Road, Chengdu 610041, People's Republic of China.
authors.forename: C
authors.initials: C
authors.lastname: Wang
authors.affiliation: The State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital and College of Life Science, Sichuan University, No. 17 People's South Road, Chengdu 610041, People's Republic of China.
authors.forename: Y
authors.initials: Y
authors.lastname: Wei
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D020287:In Situ Nick-End Labeling; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008819:Mice, Nude; D024101:Mitochondrial Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019311:Staurosporine / Q000031:analogs & derivatives* / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; C412403:DIABLO protein, human; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; C488588:PUMA protein, mouse; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; D051020:bcl-X Protein; C054852:7-hydroxystaurosporine; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3; D053453:Caspase 9; D019311:Staurosporine