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Chemical, Physical and Biological Triggers of Evolutionary Conserved Bcl-xL-Mediated Apoptosis

Background: The evidence that pan-Bcl-2 or Bcl-xL-specific inhibitors prematurely kill virus-infected or RNA/DNA-transfected cells provides rationale for investigating these apoptotic inducers further. We hypothesized that not only invasive RNA or DNA (biological factors) but also DNA/RNA-damaging c...

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Detalles Bibliográficos
Autores principales: Ianevski, Aleksandr, Kulesskiy, Evgeny, Krpina, Klara, Lou, Guofeng, Aman, Yahyah, Bugai, Andrii, Aasumets, Koit, Akimov, Yevhen, Bulanova, Daria, Gildemann, Kiira, Arutyunyan, Albert F., Susova, Olga Yu., Zhuze, Alexei L., Ji, Ping, Wang, Wei, Holien, Toril, Bugge, Marit, Zusinaite, Eva, Oksenych, Valentyn, Lysvand, Hilde, Gerhold, Joachim M., Bjørås, Magnar, Johansen, Pål, Waage, Anders, Heckman, Caroline A., Fang, Evandro F., Kainov, Denis E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352625/
https://www.ncbi.nlm.nih.gov/pubmed/32630560
http://dx.doi.org/10.3390/cancers12061694
Descripción
Sumario:Background: The evidence that pan-Bcl-2 or Bcl-xL-specific inhibitors prematurely kill virus-infected or RNA/DNA-transfected cells provides rationale for investigating these apoptotic inducers further. We hypothesized that not only invasive RNA or DNA (biological factors) but also DNA/RNA-damaging chemical or physical factors could trigger apoptosis that have been sensitized with pan-Bcl-2 or Bcl-xL-specific agents; Methods: We tested chemical and physical factors plus Bcl-xL-specific inhibitor A-1155463 in cells of various origins and the small roundworms (C. elegans); Results: We show that combination of a A-1155463 along with a DNA-damaging agent, 4-nitroquinoline-1-oxide (4NQO), prematurely kills cells of various origins as well as C. elegans. The synergistic effect is p53-dependent and associated with the release of Bad and Bax from Bcl-xL, which trigger mitochondrial outer membrane permeabilization. Furthermore, we found that combining Bcl-xL-specific inhibitors with various chemical compounds or physical insults also induced cell death; Conclusions: Thus, we were able to identify several biological, chemical and physical triggers of the evolutionarily conserved Bcl-xL-mediated apoptotic pathway, shedding light on strategies and targets for novel drug development.