Caspase-9 mediates Puma activation in UCN-01-induced apoptosis

• Published in: Cell death & disease Vol. 5; no. 10; p. e1495
• Main Authors: Nie, C, Luo, Y, Zhao, X, Luo, N, Tong, A, Liu, X, Yuan, Z, Wang, C, Wei, Y
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-10-2014; Springer Nature B.V; Nature Publishing Group
• Subjects: 13; 13/1; 13/109; 13/2; 13/89; 13/95; 14/32; 14/34; 631/67/1059; 631/80/82/23; 631/80/86; Animals; Antibodies; Apoptosis - drug effects; Apoptosis Regulatory Proteins - metabolism; bcl-X Protein - metabolism; Biochemistry; Biomedical and Life Sciences; Caspase 3 - metabolism; Caspase 9 - metabolism; Cell Biology; Cell Culture; Cell Line, Tumor; Cell Proliferation - drug effects; Enzyme Activation - drug effects; Female; Fibroblasts - cytology; Forkhead Box Protein O3; Forkhead Transcription Factors - metabolism; Humans; Immunology; In Situ Nick-End Labeling; Intracellular Signaling Peptides and Proteins - metabolism; Life Sciences; Mice, Nude; Mitochondrial Proteins - metabolism; Original; original-article; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Staurosporine - analogs & derivatives; Staurosporine - pharmacology; Tumor Suppressor Protein p53 - metabolism; Tumor Suppressor Proteins - metabolism; X-Linked Inhibitor of Apoptosis Protein - metabolism; Xenograft Model Antitumor Assays
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2014.461

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.