Bufotalin sensitizes death receptor-induced apoptosis via Bid- and STAT1-dependent pathways.

Abstract

Tumor necrosis factor-alpha (TNF-α) and TNF-related apoptosis-inducing ligand (TRAIL) are apoptosis-inducing ligands that stimulate death receptors. In this study, we investigated the effects of bufotalin, a major compound in toad venom, on sensitizing TNF-α and TRAIL-induced apoptosis of HeLa cells. Bufotalin promoted death receptor-mediated cell death, especially TRAIL-induced apoptosis, through activation of caspase-3 and PARP-1. Mitochondrial Bid-dependent pathway was activated in TNF-α-induced cell death. Cotreatment of bufotalin with TRAIL resulted in the downregulation of anti-apoptotic proteins, including Bcl-XL, Mcl-1, survivin and XIAP, and the up-regulation of MAPKs and TRAIL receptor DR5. In addition, phosphorylation of STAT1 was strongly inhibited by bufotalin. Moreover, DR5 expression was induced by knocking down the STAT1 expression. Moreover, the TRAIL-induced apoptotic response was promoted by STAT1 siRNA. Our results demonstrated that bufotalin is a powerful sensitizer of death receptor-induced apoptosis in cancer cells.

• Authors: Pornthip Waiwut, Akiko Inujima, Hiroki Inoue, Ikuo Saiki, Hiroaki Sakurai
• Journal: International journal of oncology (Int J Oncol) Vol. 40 Issue 1 Pg. 203-8 (Jan 2012) ISSN: 1791-2423 [Electronic] Greece
• PMID: 21887462 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• BH3 Interacting Domain Death Agonist Protein
• BID protein, human
• Bufanolides
• RNA, Messenger
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• Recombinant Proteins
• STAT1 Transcription Factor
• STAT1 protein, human
• TNF-Related Apoptosis-Inducing Ligand
• TNFSF10 protein, human
• Tumor Necrosis Factor-alpha
• bufotalin

Topics

• Apoptosis (drug effects)
• BH3 Interacting Domain Death Agonist Protein (metabolism)
• Bufanolides (pharmacology)
• Drug Synergism
• HeLa Cells
• Humans
• Phosphorylation (drug effects)
• RNA, Messenger (biosynthesis, genetics)
• Receptors, TNF-Related Apoptosis-Inducing Ligand (biosynthesis, genetics)
• Recombinant Proteins (pharmacology)
• STAT1 Transcription Factor (metabolism)
• Signal Transduction (drug effects)
• TNF-Related Apoptosis-Inducing Ligand (antagonists & inhibitors, pharmacology)
• Tumor Necrosis Factor-alpha (pharmacology)