Journal
BIOLOGICAL CHEMISTRY
Volume 393, Issue 7, Pages 647-658Publisher
WALTER DE GRUYTER GMBH
DOI: 10.1515/hsz-2011-0279
Keywords
apoptosis; Bcl-2; benzophenanthridine alkaloids; LC3; necrostatin-1; RIP1
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Funding
- Czech Science Foundation [525/08/0819]
- Ministry of Education of the Czech Republic [LC06077, LH12176]
- Ministry of Health of the Czech Republic [NS10236-3/2009]
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We show that the plant quaternary benzo[c]phenanthridine alkaloid sanguilutine (SL) is a strong inducer of caspase-independent non-apoptotic death in human melanoma cells. Necrostatin-1, a specific inhibitor of necroptosis, completely reversed the cytotoxic effect of SL, suggesting that necroptosis was a predominant type of cell death induced by SL in these cells. In addition, we showed that SL can trigger an autophagic response, as confirmed by GFP-LC3 puncta formation and LC3-II accumulation. Interestingly, we observed a significant decrease in the viability of melanoma cells treated with combination of autophagy inhibitors (3-methyladenine, bafilomycin-A1 and LY294002) and SL. Our results further indicated that autophagy may serve as a pro-survival mechanism, delaying the induction of necroptosis in melanoma cells. The ability of SL to induce caspase-independent non-apoptotic cell death (necroptosis) suggests its possible therapeutic potential in the treatment of apoptosis-resistant melanoma tumours. Furthermore, SL might serve as a useful tool for studying the mechanisms of necroptosis and autophagy induction and the interplay between these two processes.
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