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

Raghu Gogada, Michael Amadori, Honghao Zhang, Anthony Jones, Alissa Verone, Jason Pitarresi, Sirisha Jandhyam, Varun Prabhu, Jennifer D. Black, Dhyan Chandra

Research output: Contribution to journalArticle

48 Scopus citations

Abstract

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 for 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 pro-apoptotic proteins, such as Bax, Bak, Bid and Bim. Cross-linking 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 for p21 in Apaf-1-dependent caspase activation and apoptosis. Together, our findings identify Apaf-1, Bax and p21 as novel potential targets for curcumin or curcumin-based anticancer agents.

Original languageEnglish (US)
Pages (from-to)4128-4137
Number of pages10
JournalCell Cycle
Volume10
Issue number23
DOIs
StatePublished - Dec 1 2011

Keywords

  • Apaf-1
  • Caspase
  • Curcumin
  • Cytochrome c
  • Mitochondria
  • p21

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Curcumin induces Apaf-1-dependent, p21-mediated caspase activation and apoptosis'. Together they form a unique fingerprint.

  • Cite this

    Gogada, R., Amadori, M., Zhang, H., Jones, A., Verone, A., Pitarresi, J., Jandhyam, S., Prabhu, V., Black, J. D., & Chandra, D. (2011). Curcumin induces Apaf-1-dependent, p21-mediated caspase activation and apoptosis. Cell Cycle, 10(23), 4128-4137. https://doi.org/10.4161/cc.10.23.18292