Chapter Nine Lysosomes in Apoptosis

Ivanova, Saška; Repnik, Urška; Bojić, Lea; Petelin, Ana; Turk,; Turk, Boris

doi:10.1016/s0076-6879(08)01409-2

Cited by 80 publications

(61 citation statements)

References 65 publications

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“…24 The cathepsins as one of the largest lysosomal protease groups are considered as crucial, and the most abundant CB, CD, and CL are often used as biomarkers for lysosomal damage. 12, 24 Using specific antibodies against the different cathepsins, we were able to detect the release of mature CB and CD from the lysosomes after 24 h of exposure to EnnB. Since gel electrophoresis had been conducted under denaturing and reducing conditions, the two-chain forms had been separated, and only bands the size of the heavy chains were determined.…”

Section: Discussionmentioning

confidence: 99%

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Lysosomes as a Possible Target of Enniatin B-Induced Toxicity in Caco-2 Cells

Ivanova

Egge-Jacobsen

Solhaug

et al. 2012

Chem. Res. Toxicol.

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Enniatins are cyclic hexadepsipeptidic mycotoxins with ionophoric, antibiotic, and insecticidal activity. Enniatin B (EnnB), the most important analogue, is produced by many Fusarium species and is a common contaminant in grain-based foods. The compound's cytotoxic potential has been shown in different experiments; however, the mode of action has not been detailed so far. In the present study, several mutually confirmative experiments have been performed indicating that EnnB-initiated cytotoxicity could be connected with lysosomal membrane permeabilization (LMP). Lysosomal functionality, as assessed by the Neutral Red assay, was already affected after 3 h of toxin exposure. After 24 h, cell proliferation was decreased, and there was indication for a cell cycle arrest in the G(2)/M phase leading to the initiation of apoptosis or necrosis. Intracellular ROS-production was observed. However, antioxidants did not alter the observed EnnB-induced loss of lysosomal functionality leading to the conclusion that ROS was not an initial factor but one produced later in the event cascade. The collected data suggested that lysosomal destabilization is an upstream event in EnnB-initiated cytotoxicity followed by a certain extent of translocation of cathepsins into the cytosol, which was observed using immunological and proteomic methods. It appeared that cell death induced by EnnB was delayed and occurred not as a massive lysosomal breakdown but was probably progressing and leading to partial and selective LMP, starting a nonapoptotic cell death pathway with morphological features that had been previously considered as necrotic. The molecular mechanism of EnnB-triggered lysosomal destabilization, and the cellular processes leading to mitochondrial permeabilization and cell death are still unknown. They may, however, be connected to the compound's ionophoric properties.

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Section: Discussionmentioning

confidence: 99%

“…E-64d and Pep A (both 5 mg/mL stock in DMSO) were added at a final concentration of 20 μM and 40 μM, respectively. 24 The same concentration of inhibitor was present during the experiment. The DMSO concentration in the incubation medium was 0.14% and 0.55%, respectively (v/v).…”

Section: Methodsmentioning

confidence: 99%

Lysosomes as a Possible Target of Enniatin B-Induced Toxicity in Caco-2 Cells

Ivanova

Egge-Jacobsen

Solhaug

et al. 2012

Chem. Res. Toxicol.

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show abstract

“…Importantly, the mild detergent digitonin was utilized to specifically avoid dissolving the lysosomal membrane (20). After blocking with 5% BSA, immunofluorescence was performed by incubation (16 h, 4°C) with FITC-conjugated anti-Pgp (1:100, catalog no.…”

Section: Methodsmentioning

confidence: 99%

Di-2-pyridylketone 4,4-Dimethyl-3-thiosemicarbazone (Dp44mT) Overcomes Multidrug Resistance by a Novel Mechanism Involving the Hijacking of Lysosomal P-Glycoprotein (Pgp)

Jansson

Yamagishi

Arvind

et al. 2015

Journal of Biological Chemistry

111

248

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“…A critical step in apoptosis is caspase activation, which can be achieved in several ways, including death receptor activation and mitochondrial permeabilization or through the action of granzymes, which are released from secretory granules of NK mitochondria, which are the central organelles in apoptosis (9,10). Although lysosomes and lysosomal cathepsins were also suggested to play a role in apoptosis (3,11), their involvement seems to be of lesser importance for apoptotic progression and limited to specific stimuli, such as lysosomal detergent action, ROS linked with redox-active iron, and several anticancer drugs (12)(13)(14). Nevertheless, lysosomes and lysosomal cathepsins might play an important role in neurodegeneration and aging, mediated primarily by oxidative stress (13,15).…”

Section: Cell Death and Lysosomesmentioning

confidence: 99%