Method to identify physical, chemical and biological factors that trigger Bcl-xL-mediated apoptosis

Ianevski, A.; Kulesskiy, E.; Krpina, K.; Lou, G.; Aman, Y.; Bugai, A.; Aasumets, K.; Akimov, Y.; Bulanova, D.; Gildemann, K.; Arutyunyan, A. F.; Susova, O. Y.; Zhuze, A. L.; Oksenych, V.; Lysvand, H.; Gerhold, J.; Bjoras, M.; Waage, A.; Johansen, P.; Heckman, C.; Fang, E. F.; Kainov, D. E.

doi:10.1101/2020.01.13.904714

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bioRxiv · 10.1101/2020.01.13.904714

Method to identify physical, chemical and biological factors that trigger Bcl-xL-mediated apoptosis

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Abstract

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. Here, we show that Bcl-xL-specific agent A-1155463 prematurely kills cells of different origins and the small roundworms (C. elegans), when combined with DNA-damaging agent 4-nitroquinoline-1-oxide (4NQO). The synergistic effect of 4NQO-A-1155463 combination was p53-dependent, was associated with the release of Bad and Bax from Bcl-xL, which triggered mitochondrial outer membrane permeabilization (MOMP). Combinations of Bcl-xL-specific inhibitors with certain anticancer compounds or physical insults also killed cells. Collectively, our results suggest that biological, chemical and physical factors trigger evolutionary conserved Bcl-xL-mediated apoptotic pathway.

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Ianevski, A., Kulesskiy, E., Krpina, K., Lou, G., Aman, Y., Bugai, A., Aasumets, K., Akimov, Y., Bulanova, D., Gildemann, K., Arutyunyan, A. F., Susova, O. Y., Zhuze, A. L., Oksenych, V., Lysvand, H., Gerhold, J., Bjoras, M., Waage, A., Johansen, P., Heckman, C., Fang, E. F., Kainov, D. E.. 2020-01-13. Method to identify physical, chemical and biological factors that trigger Bcl-xL-mediated apoptosis. https://doi.org/10.1101/2020.01.13.904714

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