Curcumin induces Apaf-1-dependent, p21-mediated caspase activation and apoptosis

• Published in: Cell cycle (Georgetown, Tex.) Vol. 10; no. 23; pp. 4128 - 4137
• Main Authors: Gogada, Raghu, Amadori, Michael, Zhang, Honghao, Jones, Anthony, Verone, Alissa, Pitarresi, Jason, Jandhyam, Sirisha, Prabhu, Varun, Black, Jennifer D., Chandra, Dhyan
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01.12.2011; Landes Bioscience
• Subjects: Amino Acid Chloromethyl Ketones - pharmacology; Apoptosis; Apoptotic Protease-Activating Factor 1 - genetics; Apoptotic Protease-Activating Factor 1 - metabolism; bcl-2-Associated X Protein - genetics; bcl-2-Associated X Protein - metabolism; Binding; Biology; Bioscience; Calcium; Cancer; Caspase 3 - genetics; Caspase 3 - metabolism; Caspase Inhibitors; Cell; Curcumin - pharmacology; Cycle; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Cytochromes c - genetics; Cytochromes c - metabolism; Cytosol - drug effects; Cytosol - metabolism; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme Inhibitors - pharmacology; Fluorescent Antibody Technique; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; HCT116 Cells; Humans; Jurkat Cells; Landes; Lentivirus - genetics; Lentivirus - metabolism; Mitochondria - drug effects; Mitochondria - genetics; Mitochondria - metabolism; Mitochondrial Membranes - drug effects; Mitochondrial Membranes - metabolism; Organogenesis; Proteins; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism
• ISSN: 1538-4101; 1551-4005
• DOI: 10.4161/cc.10.23.18292

Previous studies have demonstrated that curcumin induces mitochondria-mediated apoptosis. However, understanding of the molecular mechanisms underlying curcumin-induced cell death remains limited. In this study, we demonstrate that curcumin treatment of cancer cells caused dose- and time-dependent caspase-3 activation, which is required for apoptosis as confirmed using the pan caspase inhibitor, z-VAD. Knockdown experiments and knockout cells excluded a role of caspase-8 in curcumin-induced caspase-3 activation. In contrast, Apaf-1 deficiency or silencing inhibited the activity of caspase-3, pointing to a requisite role of Apaf-1 in curcumin-induced apoptotic cell death. Curcumin treatment led to Apaf-1 upregulation both at the protein and mRNA levels. Cytochrome c release from mitochondria to the cytosol in curcumin-treated cells was associated with upregulation of proapoptotic proteins such as Bax, Bak, Bid, and Bim. Crosslinking experiments demonstrated Bax oligomerization during curcumin-induced apoptosis, suggesting that induced expression of Bax, Bid, and Bim causes Bax-channel formation on the mitochondrial membrane. The release of cytochrome c was unaltered in p53-deficient cells, whereas absence of p21 blocked cytochrome c release, caspase activation, and apoptosis. Importantly, p21-deficiency resulted in reduced expression of Apaf-1 during curcumin treatment, indicating a requirement of p21 in Apaf-1 dependent caspase activation and apoptosis. Together, our findings demonstrate that Apaf-1, Bax, and p21 as novel potential targets for curcumin or curcumin-based anticancer agents.