Abstract
ABT-263 and its structural analogues ABT-199 and ABT-737 inhibit B-cell lymphoma 2 (Bcl-2), BCL2L1 long isoform (Bcl-xL) and BCL2L2 (Bcl-w) proteins and promote cancer cell death. Here, we show that at non-cytotoxic concentrations, these small molecules accelerate the deaths of non-cancerous cells infected with influenza A virus (IAV) or other viruses. In particular, we demonstrate that ABT-263 altered Bcl-xL interactions with Bcl-2 antagonist of cell death (Bad), Bcl-2-associated X protein (Bax), uveal autoantigen with coiled-coil domains and ankyrin repeats protein (UACA). ABT-263 thereby activated the caspase-9-mediated mitochondria-initiated apoptosis pathway, which, together with the IAV-initiated caspase-8-mediated apoptosis pathway, triggered the deaths of IAV-infected cells. Our results also indicate that Bcl-xL, Bcl-2 and Bcl-w interact with pattern recognition receptors (PRRs) that sense virus constituents to regulate cellular apoptosis. Importantly, premature killing of IAV-infected cells by ABT-263 attenuated the production of key pro-inflammatory and antiviral cytokines. The imbalance in cytokine production was also observed in ABT-263-treated IAV-infected mice, which resulted in an inability of the immune system to clear the virus and eventually lowered the survival rates of infected animals. Thus, the results suggest that the chemical inhibition of Bcl-xL, Bcl-2 and Bcl-w could potentially be hazardous for cancer patients with viral infections.
Highlights
The adverse effects of ABT-263 L Kakkola et al activates caspase-8.4,5 Active caspase-8 cleaves BH3-interacting domain death agonist (Bid).[6]
Replication of several important human microbes, such as the influenza A virus (IAV), hepatitis B virus, hepatitis C virus, Epstein–Barr virus, vesicular stomatitis virus, coronavirus, Kaposi’s sarcoma-associated herpes virus and human immunodeficiency virus depend on B-cell lymphoma 2 (Bcl-2), Bcl-xL- and Bcl-w-mediated mitochondria-initiated apoptosis.[8,9,10,11,12,13,14,15,16]
We hypothesised that the chemical inhibitors of Bcl-2, Bcl-xL and Bcl-w could accelerate the death of virus-infected cells by enhancing caspase-mediated cross-talk between mitochondria and death receptor apoptosis pathways
Summary
The adverse effects of ABT-263 L Kakkola et al activates caspase-8.4,5 Active caspase-8 cleaves BH3-interacting domain death agonist (Bid).[6] Cleaved Bid facilitates the mitochondrial apoptosis pathway and accelerates cancer cell death.[7]. Replication of several important human microbes, such as the influenza A virus (IAV), hepatitis B virus, hepatitis C virus, Epstein–Barr virus, vesicular stomatitis virus, coronavirus, Kaposi’s sarcoma-associated herpes virus and human immunodeficiency virus depend on Bcl-2-, Bcl-xL- and Bcl-w-mediated mitochondria-initiated apoptosis.[8,9,10,11,12,13,14,15,16] In addition to mitochondria-initiated apoptosis, the replication of these microbes is associated with the caspase-8-FADD (FAS-associating death domain-containing protein)-mediated apoptosis pathway.[17] We hypothesised that the chemical inhibitors of Bcl-2, Bcl-xL and Bcl-w could accelerate the death of virus-infected cells by enhancing caspase-mediated cross-talk between mitochondria and death receptor apoptosis pathways. We show that anticancer ABT-263, ABT-737 and ABT-199 accelerate the death of non-cancerous mammalian cells infected with IAV and other viruses through the mutual amplification of the caspase-9-mediated mitochondriainitiated apoptosis by the IAV-initiated caspase-8-mediated apoptosis. Our results suggest that ABT-263, ABT-737 and ABT-199 may be hazardous for cancer patients with viral infections
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