Chemical, Physical and Biological Triggers of Evolutionary Sonserved Bcl-xL-Mediated Apoptosis
| Autor: | Alexei L. Zhuze, Valentyn Oksenych, Koit Aasumets, Klara Krpina, Evandro Fei Fang, Eva Zusinaite, Denis E. Kainov, Ping Ji, Yahyah Aman, Magnar Bjørås, Pål Johansen, Albert F. Arutyunyan, Marit Bugge, Wei Wang, Caroline A. Heckman, Guofeng Lou, Hilde Lysvand, Kiira Gildemann, Andrii Bugai, Joachim M. Gerhold, Toril Holien, Yevhen Akimov, Anders Waage, Aleksandr Ianevski, Evgeny Kulesskiy, Daria Bulanova, Olga Yu. Susova |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Programmed cell death oncolytics Bcl-xL lcsh:RC254-282 Article 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Mitophagy Inducer 030304 developmental biology 0303 health sciences Mitochondrial outer membrane permeabilization biology navitoclax Chemistry apoptosis RNA lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens In vitro 3. Good health Cell biology 030104 developmental biology Oncology Apoptosis 030220 oncology & carcinogenesis biology.protein DNA Obatoclax |
| Zdroj: | Cancers Volume 12 Issue 6 Cancers, Vol 12, Iss 1694, p 1694 (2020) |
| ISSN: | 2072-6694 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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