Insight into redox regulation of apoptosis in cancer cells with multiparametric live-cell microscopy

Shirmanova, M.V.; Gavrina, A.I.; Kovaleva, T.F.; Dudenkova, V.V.; Zelenova, E.E.; Shcheslavskiy, V.I.; Mozherov, A.M.; Snopova, L.B.; Lukyanov, K.A.; Zagaynova, E.V.

Авторы: Shirmanova Marina V., Gavrina Alena I., Kovaleva Tatiana F., Dudenkova Varvara V., Zelenova Ekaterina E., Shcheslavskiy Vladislav I., Mozherov Artem M., Snopova Ludmila B., Lukyanov Konstantin A., Zagaynova Elena V.
Журнал: Scientific reports
Том: 12
Номер: 1
Год издания: 2022
Издательство: Nature Publishing Group
Местоположение издательства: United Kingdom
Номер статьи: 4476
DOI: 10.1038/s41598-022-08509-1
Аннотация: Cellular redox status and the level of reactive oxygen species (ROS) are important regulatorsof apoptotic potential, playing a crucial role in the growth of cancer cell and their resistance toapoptosis. However, the relationships between the redox status and ROS production during apoptosisremain poorly explored. In this study, we present an investigation on the correlations between theproduction of ROS, the redox ratio FAD/NAD(P)H, the proportions of the reduced nicotinamidecofactors NADH and NADPH, and caspase-3 activity in cancer cells at the level of individual cells.Two-photon excitation fluorescence lifetime imaging microscopy (FLIM) was applied to monitorsimultaneously apoptosis using the genetically encoded sensor of caspase-3, mKate2-DEVD-iRFP, andthe autofluorescence of redox cofactors in colorectal cancer cells upon stimulation of apoptosis with staurosporine, cisplatin or hydrogen peroxide. We found that, irrespective of the apoptotic stimulus used, ROS accumulation correlated well with both the elevated pool of mitochondrial, enzyme bound NADH and caspase-3 activation. Meanwhile, a shift in the contribution of bound NADH could develop independently of the apoptosis, and this was observed in the case of cisplatin. An increase in the proportion of bound NADPH was detected only in staurosporine-treated cells, this likely being associated with a high level of ROS production and their resulting detoxification. The results of the study favor the discovery of new therapeutic strategies based on manipulation of the cellular redox balance, which could help improve the anti-tumor activity of drugs and overcome apoptotic resistance.
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Insight into redox regulation of apoptosis in cancer cells with multiparametric live-cell microscopyстатья

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