10779/rcsi.10792433.v1
Barbara Köhler
Barbara
Köhler
Sergio Anguissola
Sergio
Anguissola
Caoimhín G. Concannon
Caoimhín G.
Concannon
Markus Rehm
Markus
Rehm
Donat Kögel
Donat
Kögel
Jochen HM Prehn
Jochen HM
Prehn
Bid participates in genotoxic drug-induced apoptosis of HeLa cells and is essential for death receptor ligands' apoptotic and synergistic effects.
Royal College of Surgeons in Ireland
2019
Antigens
CD95
Antineoplastic Agents
Apoptosis
BH3 Interacting Domain Death Agonist Protein
Caspase 10
Caspase 8
Doxorubicin
Endoplasmic Reticulum
Etoposide
HeLa Cells
Humans
Ligands
Organoplatinum Compounds
TNF-Related Apoptosis-Inducing Ligand
Tunicamycin
Physiology
Medical Physics
2019-11-22 17:02:22
Journal contribution
https://repository.rcsi.com/articles/journal_contribution/Bid_participates_in_genotoxic_drug-induced_apoptosis_of_HeLa_cells_and_is_essential_for_death_receptor_ligands_apoptotic_and_synergistic_effects_/10792433
<p>BACKGROUND: 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.</p>
<p>METHODOLOGY/PRINCIPAL FINDINGS: 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.</p>
<p>CONCLUSIONS/SIGNIFICANCE: 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.</p>