Show simple item record

dc.creatorStamenković, Marina
dc.creatorJanjetović, Kristina
dc.creatorPaunović, Verica
dc.creatorĆirić, Darko
dc.creatorKravić-Stevović, Tamara
dc.creatorTrajković, Vladimir
dc.date.accessioned2019-08-28T09:40:12Z
dc.date.available2900-01-01
dc.date.issued2019
dc.identifier.urihttps://www.sciencedirect.com/science/article/pii/S0014299919304923?via%3Dihub
dc.identifier.urihttps://ibiss-r.rcub.bg.ac.rs/handle/123456789/3448
dc.description.abstractWe performed a comparative analysis of molecular cytotoxic mechanisms of lysosomal autophagy inhibitors bafilomycin A1, chloroquine, and ammonium chloride in B16 mouse melanoma cells. All agents caused oxidative stress, mitochondrial depolarization, and caspase-dependent apoptotic death, which was not affected by genetic inactivation of autophagy. Cathepsin inhibition reduced only the cytotoxicity of chloroquine, indicating its ability to cause lysosomal membrane permeabilization. Bafilomycin reduced the mRNA levels of anti-apoptotic Bcl-2, while chloroquine and ammonium chloride increased the mRNA expression of pro-apoptotic Pten and Puma, as well as anti-apoptotic Bcl-xL. Ammonium chloride additionally increased the mRNA expression of pro-apoptotic Bim and p53. All three agents decreased the activity of mechanistic target of rapamycin (mTOR) and increased the activation of p38 mitogen-activated protein kinase (MAPK). Chloroquine and ammonium chloride additionally stimulated the phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), respectively, while only bafilomycin increased the phosphorylation of the energy sensor AMP-activated protein kinase (AMPK). mTOR activator leucine did not affect the cytotoxicity of lysosomal inhibitors. p38 MAPK inhibitor SB203580 reduced the cytotoxicity of bafilomycin but increased that of chloroquine and ammonium chloride. The pharmacological inhibition of ERK1/2, JNK, and AMPK potentiated the cytotoxicity of chloroquine, ammonium chloride, and bafilomycin, respectively. The observed mechanistic differences were associated with antagonistic interactions of lysosomal inhibitors in B16 cell killing. In conclusion, all investigated lysosomal inhibitors cause autophagy-independent mitochondrial dysfunction and apoptotic death, but differ in the ability to affect lysosomal permeabilization, balance between pro- and anti-apoptotic molecules of Bcl-2 family, and MAPK/AMPK signaling.
dc.relationinfo:eu-repo/grantAgreement/MESTD/Integrated and Interdisciplinary Research (IIR or III)/41025/RS//
dc.rightsrestrictedAccess
dc.sourceEuropean Journal of Pharmacology
dc.subjectAMPK
dc.subjectApoptosis
dc.subjectAutophagy inhibitors
dc.subjectBcl-2
dc.subjectLysosomes
dc.subjectMAP kinases
dc.titleComparative analysis of cell death mechanisms induced by lysosomal autophagy inhibitors.
dc.typearticleen
dc.rights.licenseARR
dcterms.abstractПауновић, Верица; Јањетовић, Кристина; Стаменковић, Марина; Ћирић, Дарко; Кравић-Стевовић, Тамара; Трајковић, Владимир;
dc.rights.holder© 2019 Elsevier B.V.
dc.citation.volume859
dc.identifier.doi10.1016/j.ejphar.2019.172540
dc.identifier.pmid31310755
dc.identifier.scopus2-s2.0-85069683163
dc.identifier.wos000477819500027
dc.citation.apaStamenkovic, M., Janjetovic, K., Paunovic, V., Ciric, D., Kravic-Stevovic, T., & Trajkovic, V. (2019). Comparative analysis of cell death mechanisms induced by lysosomal autophagy inhibitors. European Journal of Pharmacology, 859, 172540.
dc.citation.vancouverStamenkovic M, Janjetovic K, Paunovic V, Ciric D, Kravic-Stevovic T, Trajkovic V. Comparative analysis of cell death mechanisms induced by lysosomal autophagy inhibitors. Eur J Pharmacol. 2019;859:172540.
dc.citation.spage172540
dc.type.versionpublishedVersion
dc.citation.rankM22


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record