Bid Participates in Genotoxic Drug-Induced Apoptosis of HeLa Cells and Is Essential for Death Receptor Ligands' Apoptotic and Synergistic Effects
Open Access
- 30 July 2008
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 3 (7), e2844
- https://doi.org/10.1371/journal.pone.0002844
Abstract
The BH3-only protein Bid is an important component of death receptor-mediated caspase activation. Bid is cleaved by caspase-8 or -10 into t-Bid, which translocates to mitochondria and triggers the release of caspase-activating factors. Bid has also been reported to be cleaved by other proteases. To test the hypothesis that Bid is a central mediator of stress-induced apoptosis, we investigated the effects of a small molecule Bid inhibitor on stress-induced apoptosis, and generated HeLa cells deficient for Bid. Stable knockdown of bid lead to a pronounced resistance to Fas/CD95- and TRAIL-induced caspase activation and apoptosis, and significantly increased clonogenic survival. While Bid-deficient cells were equally sensitive to ER stress-induced apoptosis, they showed moderate, but significantly reduced levels of apoptosis, as well as increased clonogenic survival in response to the genotoxic drugs Etoposide, Oxaliplatin, and Doxorubicin. Similar effects were observed using the Bid inhibitor BI6C9. Interestingly, Bid-deficient cells were dramatically protected from apoptosis when subtoxic concentrations of ER stressors, Etoposide or Oxaliplatin were combined with subtoxic TRAIL concentrations. Our data demonstrate that Bid is central for death receptor-induced cell death and participates in anti-cancer drug-induced apoptosis in human cervical cancer HeLa cells. They also show that the synergistic effects of TRAIL in combination with either ER stressors or genotoxic anti-cancer drugs are nearly exclusively mediated via an increased activation of Bid-induced apoptosis signalling.Keywords
This publication has 81 references indexed in Scilit:
- Mitochondrial Membrane Permeabilization in Cell DeathPhysiological Reviews, 2007
- Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamiliesNature, 2006
- Structure–activity relationships by interligand NOE-based design and synthesis of antiapoptotic compounds targeting BidProceedings of the National Academy of Sciences of the United States of America, 2006
- Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family membersCancer Cell, 2006
- The BH3-only protein, PUMA, is involved in oxaliplatin-induced apoptosis in colon cancer cellsBiochemical Pharmacology, 2006
- Mcl-1 Interacts with Truncated Bid and Inhibits Its Induction of Cytochrome c Release and Its Role in Receptor-mediated ApoptosisJournal of Biological Chemistry, 2006
- Real Time Single Cell Analysis of Bid Cleavage and Bid Translocation during Caspase-dependent and Neuronal Caspase-independent ApoptosisJournal of Biological Chemistry, 2006
- BID as a Double Agent in Cell Life and DeathCell Cycle, 2006
- Structural Model of the BCL-w−BID Peptide Complex and Its Interactions with Phospholipid Micelles,Biochemistry, 2006
- Essential Roles of the Bcl-2 Family of Proteins in Caspase-2-induced ApoptosisJournal of Biological Chemistry, 2005