Chemical, Physical and Biological Triggers of Evolutionary Sonserved Bcl-xL-Mediated Apoptosis
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 Fei; Kainov, Denis
Journal article, Peer reviewed
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Original versionCancers. 2020, 12 (6), 1-19. 10.3390/cancers12061694
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.