Effect of carboxylic ionophores on lysosomal protein degradation in rat hepatocytes☆
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Polyethers isolated from the marine actinobacterium Streptomyces cacaoi inhibit autophagy and induce apoptosis in cancer cells
2019, Chemico-Biological InteractionsCitation Excerpt :Polyether ionophores have recently gathered attention in autophagy inhibition. It was reported that Mon and Nig treatment caused accumulation of autophagic vacuoles inside the cell [11] by inhibiting the terminal fusion stage of autophagy pathway along with the accumulation of autophagy flux markers LC3-II and p62 [12,13]. In addition, two polyether antibiotics, viz. salinomycin and maduramicin, were reported to inhibit the autophagic flux in several cancer cell lines [14,15].
Cytotoxicity of anticancer candidate salinomycin and identification of its metabolites in rat cell cultures
2018, Toxicology in VitroCitation Excerpt :SAL impairs the flow of ions (K+/Na+) through cellular membranes, which is responsible for both pharmacological and toxicological action. It leads to Ca2+ overload within cells followed by decreased cellular energy and inhibits lysosomal protein degradation by affecting pH inside the organelle (Grinde, 1983; Boehmerle and Endres, 2011; Sommer et al., 2016; Zou et al., 2017). The determined median effective concentrations of the ionophore (EC50 < 0.39 μg/ml) alone or in co-action with tiamulin or prednisolone confirm strong inhibition of lysosomal activity.
Intracellular pH modulates autophagy and mitophagy
2016, Journal of Biological ChemistryCitation Excerpt :Induction of mitophagy with the alternative compound nigericin, which induces significant acidification of cytosol but does not induce mitochondrial depolarization, suggesting that a decrease in pHcyt can be a stimulus for relocation of mitochondria to lysosomes. The role of carboxylic ionophores (including nigericin and monensin) in lysosomal protein degradation was shown previously, and interestingly monensin inhibited autophagy (29). Thus, monensin and nigericin produced opposite effects on pH and on autophagy and mitophagy that again, suggests the effect of intracellular pH on mitochondrial and protein degradation in lysosome acidification is to inhibit this process.
Nigericin-induced impairment of autophagic flux in neuronal cells is inhibited by overexpression of Bak
2012, Journal of Biological ChemistryCitation Excerpt :The structure and properties of nigericin are similar to those of monensin, although monensin has a preference for Na+ instead of K+ (25, 38). Like nigericin, monensin treatment disrupts lysosomal function (27, 39). Immunoblotting with anti-LC3 antibody and quantitative analysis showed that the time-dependent increase in LC3-II following monensin treatment was not exacerbated by the presence of chloroquine, indicating that monensin also impaired autophagic flux in MN9D cells (supplemental Fig. S3, A and B).
Disruption of lysosome function promotes tumor growth and metastasis in Drosophila
2010, Journal of Biological Chemistry
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The work was supported by a grant from A/S Norsk Varekrigsforsikrings Fond.