Anticancer compound ABT-263 accelerates apoptosis in virus-infected cells and imbalances cytokine production and lowers survival rates of infected mice

被引：45

作者：

Kakkola, L. ^{[1
]}

Denisova, O. V. ^{[1
]}

Tynell, J. ^{[2
]}

Viiliainen, J. ^{[3
]}

Ysenbaert, T. ^{[4
,5
]}

Matos, R. C. ^{[1
]}

Nagaraj, A. ^{[1
]}

Ohman, T. ^{[3
]}

Kuivanen, S. ^{[6
]}

Paavilainen, H. ^{[7
]}

Feng, L. ^{[8
]}

Yadav, B. ^{[1
]}

Julkunen, I. ^{[2
]}

Vapalahti, O. ^{[6
,9
]}

Hukkanen, V. ^{[7
]}

Stenman, J. ^{[1
,8
]}

Aittokallio, T. ^{[1
]}

Verschuren, E. W. ^{[1
]}

Ojala, P. M. ^{[3
,10
]}

Nyman, T. ^{[3
]}

Saelens, X. ^{[4
,5
]}

Dzeyk, K. ^{[11
]}

Kainov, D. E. ^{[1
]}

机构：

[1] FIMM, Inst Mol Med Finland, Helsinki 00290, Finland

[2] Natl Inst Hlth & Welf, Helsinki 00271, Finland

[3] Univ Helsinki, Inst Biotechnol, Helsinki 00014, Finland

[4] VIB, Dept Mol Biomed Res, B-9000 Ghent, Belgium

[5] Univ Ghent, Dept Biomed Mol Biol, B-9000 Ghent, Belgium

[6] Univ Helsinki, Haartman Inst, FIN-00014 Helsinki, Finland

[7] Univ Turku, Dept Virol, FIN-20520 Turku, Finland

[8] Minerva Fdn, Helsinki 00290, Finland

[9] Helsinki Univ Hosp Lab, Helsinki 00290, Finland

[10] Fdn Finnish Canc Inst, Helsinki 00290, Finland

[11] EMBL, Prote Core Facil, D-69117 Heidelberg, Germany

来源：

CELL DEATH & DISEASE | 2013年 / 4卷

基金：

芬兰科学院;

关键词：

innate immunity; apoptosis; Bcl-xL; infection; cytokines; virus; BCL-X-L; EPITHELIAL-CELLS; HUMAN PLATELETS; INFLUENZA; DEATH; INDUCTION; PROTEIN; POTENT; SALIPHENYLHALAMIDE; REPLICATION;

D O I：

10.1038/cddis.2013.267

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

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.

引用

页码：e742 / e742

页数：11

共 37 条

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