Lysosome-targeted stress reveals increased stability of lipofuscin-containing lysosomes

Stroikin, Yuri; Mild, Hanna; Johansson, Uno; Roberg, Karin; Öllinger, Karin

doi:10.1007/s11357-007-9045-9

Cited by 14 publications

(7 citation statements)

References 35 publications

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“…Under normal conditions, cathepsin D is found only in endosomes/lysosome . The permeabilization of endosomes/lysosomes’ membrane could cause the release of this protein. , In this study, the results of Western blotting indicated that this type of release was significantly higher in the cytoplasmic fractions of MCF-7/ADR cells after treatment of conjugates compared to free DOX (Figure A), providing the evidence that the integrity of endosomes/lysosomes was destabilized to a greater extent in the presence of T10-DOX and T15-DOX. Since the released cathepsin D in cytosol can further initiate apoptosis signaling pathways, apoptosis-related caspase-3 protein expression was measured.…”

Section: Resultssupporting

confidence: 54%

Acid-Sensitive Peptide-Conjugated Doxorubicin Mediates the Lysosomal Pathway of Apoptosis and Reverses Drug Resistance in Breast Cancer

Yuan

You

et al. 2015

Mol. Pharmaceutics

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The extended use of doxorubicin (DOX) could be limited because of the emergence of drug resistance associated with its treatment. To reverse the drug resistance, two thiol-modified peptide sequences HAIYPRHGGC and THRPPMWSPVWPGGC were, respectively, conjugated to DOXO-EMCH, forming a maleimide bridge in this study (i.e., T10-DOX and T15-DOX). The structures and properties of peptide-DOX conjugates were characterized using (1)H NMR, (13)C NMR, mass spectrometry, and high-performance liquid chromatography. Their stability was also evaluated. By using MCF-7/ADR cells as an in vitro model system and nude mice bearing MCF-7/ADR xenografts as an in vivo model, the ability of these novel peptide-DOX conjugates to reverse drug resistance was accessed as compared with free DOX. As a result, the IC50 values for T10-DOX and T15-DOX significantly decreased (31.6 ± 1.6 μM and 27.2 ± 0.8 μM), whereas the percentage of apoptotic cell population increased (35.4% and 39.3%). The in vivo extent of inhibition was more evident in the mice groups treated with peptide-DOX conjugates (59.6 ± 8.99% and 46.4 ± 6.63%), which had DOX primarily accumulated in tumor. These conjugates also showed a longer half-life in plasma and cleared much more slowly from the body. Furthermore, T10-DOX may be more effective than T15-DOX with a higher efficacy and a lower side effect. Most importantly, evidence was provided to support the enhanced intracellular drug accumulation and the induction of lysosomal pathway of apoptosis underlying the drug resistance. As an endosomal/lysosomal marker, cathepsin D permealized the destabilized organelle membrane and was detected in the cytoplasm, leading to the activation of the effector caspase-3 in cell apoptosis. This report is among the first to demonstrate that peptide-DOX-like conjugates promote apoptosis through the initiation of the lysosomal pathway.

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Section: Resultssupporting

confidence: 54%

Acid-Sensitive Peptide-Conjugated Doxorubicin Mediates the Lysosomal Pathway of Apoptosis and Reverses Drug Resistance in Breast Cancer

Yuan

You

et al. 2015

Mol. Pharmaceutics

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“…Many studies have reported the negative effects of accumulating lipofuscin on lysosomal activity and cellular function, but more recent studies have suggested that lysosomes can play a protective role in the oxidative stress response and suggest that lipofuscin accumulation is indicative of cellular maintenance through autophagic activity [26,27,37]. In sea urchins, an age-related accumulation of lipofuscin was seen in all tissues examined (muscle, nerve and esophagus) which reaches significance in muscle tissue of L. variegatus and S. purpuratus , esophagus tissues of S. purpuratus and nerve tissue of all three species.…”

Section: Discussionmentioning

confidence: 99%

Oxidative damage and cellular defense mechanisms in sea urchin models of aging

Anderson

Lortie

et al. 2013

Free Radical Biology and Medicine

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The free radical or oxidative stress theory of aging proposes that the accumulation of oxidative cellular damage is a major contributor to the aging process and a key determinant of species longevity. This study investigates the oxidative stress theory in a novel model for aging research, the sea urchin. Sea urchins present a unique model for the study of aging due to the existence of species with tremendously different natural life spans including some species with extraordinary longevity and negligible senescence. Cellular oxidative damage, antioxidant capacity and proteasome enzyme activities were measured in the tissues of three sea urchin species: short-lived Lytechinus variegatus, long-lived Strongylocentrotus franciscanus and Strongylocentrotus purpuratus which has an intermediate lifespan. Levels of protein carbonyls and 4-hydroxynonenal (HNE) measured in tissues (muscle, nerve, esophagus, gonad, coelomocytes, ampullae) and 8-hydroxy-2’-deoxyguanosine (8-OHdG) measured in cell-free coelomic fluid showed no general increase with age. The fluorescent age-pigment lipofuscin measured in muscle, nerve and esophagus, increased with age however it appeared to be predominantly extracellular. Antioxidant mechanisms (total antioxidant capacity, superoxide dismutase) and proteasome enzyme activities were maintained with age. In some instances, levels of oxidative damage were lower and antioxidant activity higher in cells or tissues of the long-lived species compared to the short-lived species, however further studies are required to determine the relationship between oxidative damage and longevity in these animals. Consistent with the predictions of the oxidative stress theory of aging, the results suggest that negligible senescence is accompanied by a lack of accumulation of cellular oxidative damage with age and maintenance of antioxidant capacity and proteasome enzyme activities may be important mechanisms to mitigate damage.

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“…Lysosomal stability was assessed by red AO-fluorescence, using Image-Pro Plus 6.0 software (Media Cybernetics, Rockville, MD, USA, 2006). Fluorescence intensity was expressed in arbitrary units: average pixel value per lysosome or the lysosome area [ 33 ].…”

Section: Methodsmentioning

confidence: 99%

Citreoviridin Induces Autophagy-Dependent Apoptosis through Lysosomal-Mitochondrial Axis in Human Liver HepG2 Cells

Wang

Liu

et al. 2015

Toxins

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Citreoviridin (CIT) is a mycotoxin derived from fungal species in moldy cereals. In our previous study, we reported that CIT stimulated autophagosome formation in human liver HepG2 cells. Here, we aimed to explore the relationship of autophagy with lysosomal membrane permeabilization and apoptosis in CIT-treated cells. Our data showed that CIT increased the expression of LC3-II, an autophagosome biomarker, from the early stage of treatment (6 h). After treatment with CIT for 12 h, lysosomal membrane permeabilization occurred, followed by the release of cathepsin D in HepG2 cells. Inhibition of autophagosome formation with siRNA against Atg5 attenuated CIT-induced lysosomal membrane permeabilization. In addition, CIT induced collapse of mitochondrial transmembrane potential as assessed by JC-1 staining. Furthermore, caspase-3 activity assay showed that CIT induced apoptosis in HepG2 cells. Inhibition of autophagosome formation attenuated CIT-induced apoptosis, indicating that CIT-induced apoptosis was autophagy-dependent. Cathepsin D inhibitor, pepstatin A, relieved CIT-induced apoptosis as well, suggesting the involvement of the lysosomal-mitochondrial axis in CIT-induced apoptosis. Taken together, our data demonstrated that CIT induced autophagy-dependent apoptosis through the lysosomal-mitochondrial axis in HepG2 cells. The study thus provides essential mechanistic insight, and suggests clues for the effective management and treatment of CIT-related diseases.

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Lysosome-targeted stress reveals increased stability of lipofuscin-containing lysosomes

Cited by 14 publications

References 35 publications

Acid-Sensitive Peptide-Conjugated Doxorubicin Mediates the Lysosomal Pathway of Apoptosis and Reverses Drug Resistance in Breast Cancer

Acid-Sensitive Peptide-Conjugated Doxorubicin Mediates the Lysosomal Pathway of Apoptosis and Reverses Drug Resistance in Breast Cancer

Oxidative damage and cellular defense mechanisms in sea urchin models of aging

Citreoviridin Induces Autophagy-Dependent Apoptosis through Lysosomal-Mitochondrial Axis in Human Liver HepG2 Cells

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