Cysteine Cathepsins Trigger Caspase-dependent Cell Death through Cleavage of Bid and Antiapoptotic Bcl-2 Homologues

Droga-Mazovec, Gabriela; Bojić, Lea; Petelin, Ana; Ivanova, Saška; Romih, Rok; Repnik, Urška; Salvesen, Guy S.; Stoka, Veronika; Türk, Vito; Turk, Boris

doi:10.1074/jbc.m802513200

Cited by 338 publications

(282 citation statements)

References 65 publications

(82 reference statements)

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“…If extensive, the oxidative process might propagate to the lysosomal membrane, where lipid peroxidation results in LMP and release of lysosomal contents, namely acidic hydrolases and low mass redox-active iron, into the cytoplasm. 48 Simultaneous staining by DCF and LysoTracker Red indicates that many, but not all lysosomes undergo a burst of oxidative reactions, which likely account for LMP. Importantly, this finding shows that lysosomes are differently sensitive to oxidation, probably because of different contents or redox-active iron.…”

Section: Discussionmentioning

confidence: 99%

Autophagy of metallothioneins prevents TNF-induced oxidative stress and toxicity in hepatoma cells

et al. 2015

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, tandem fluorescent microtubule-associated protein 1 light chain 3 A/B (green/red fluorescent proteins chimera); TNFRSF1A/TNFR1, tumor necrosis factor receptor superfamily member 1A; TNFRSF1B/TNFR2, tumor necrosis factor receptor superfamily member 1B.Lysosomal membrane permeabilization (LMP) induced by oxidative stress has recently emerged as a prominent mechanism behind TNF cytotoxicity. This pathway relies on diffusion of hydrogen peroxide into lysosomes containing redox-active iron, accumulated by breakdown of iron-containing proteins and subcellular organelles. Upon oxidative lysosomal damage, LMP allows relocation to the cytoplasm of low mass iron and acidic hydrolases that contribute to DNA and mitochondrial damage, resulting in death by apoptosis or necrosis. Here we investigate the role of lysosomes and free iron in death of HTC cells, a rat hepatoma line, exposed to TNF following metallothionein (MT) upregulation. Iron-binding MT does not normally occur in HTC cells in significant amounts. Intracellular iron chelation attenuates TNF and cycloheximide (CHX)-induced LMP and cell death, demonstrating the critical role of this transition metal in mediating cytokine lethality. MT upregulation, combined with starvation-activated MT autophagy almost completely suppresses TNF and CHX toxicity, while impairment of both autophagy and MT upregulation by silencing of Atg7, and Mt1a and/or Mt2a, respectively, abrogates protection. Interestingly, MT upregulation by itself has little effect, while stimulated autophagy alone depresses cytokine toxicity to some degree. These results provide evidence that intralysosomal iron-catalyzed redox reactions play a key role in TNF and CHX-induced LMP and toxicity. The finding that chelation of intralysosomal iron achieved by autophagic delivery of MT, and to some degree probably of other ironbinding proteins as well, into the lysosomal compartment is highly protective provides a putative mechanism to explain autophagy-related suppression of death by TNF and CHX.

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Section: Discussionmentioning

confidence: 99%

Autophagy of metallothioneins prevents TNF-induced oxidative stress and toxicity in hepatoma cells

et al. 2015

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“…Lysosomal cathepsins can be categorized as cysteine (cathepsins B, C, F, H, K, L, O, S, V, W and X), aspartic (cathepsins D and E) and serine (cathepsin G) proteases (Eskelinen and Saftig, 2008, Kuester et al, 2008, Turk et al, 2002. They have a pH optimum of around 5, although several of them remain active even at neutral pH from minutes (cathepsin L) to hours (cathepsin S) (Droga-Mazovec et al, 2008).…”

Section: The Role Of Lysosomes In Intracellular Iron Metabolismmentioning

confidence: 99%

The role of lysosomes in iron metabolism and recycling

Kurz

Eaton

Brunk

2011

The International Journal of Biochemistry & Cell Biology

172

134

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Iron is the most abundant transition metal in the earths crust. It cycles easily between ferric (oxidized; Fe(III)) and ferrous (reduced; Fe(II)) and readily forms complexes with oxygen, making this metal a central player in respiration and related redox processes. However, loose iron, not within heme or iron-sulfur cluster proteins, can be destructively redox-active, causing damage to almost all cellular components, killing both cells and organisms. This may explain why iron is so carefully handled by aerobic organisms. Iron uptake from the environment is carefully limited and carried out by specialized iron transport mechanisms. One reason that iron uptake is tightly controlled is that most organisms and cells cannot efficiently excrete excess iron. When even small amounts of intracellular free iron occur, most of it is safely stored in a non-redox-active form in ferritins. Within nucleated cells, iron is constantly being recycled from aged iron-rich organelles such as mitochondria and used for construction of new organelles. Much of this recycling occurs within the lysosome, an acidic digestive organelle. Because of this, most lysosomes contain relatively large amounts of redox-active iron and are therefore unusually susceptible to oxidant-mediated destabilization or rupture. In many cell types, iron transit through the lysosomal compartment can be remarkably brisk. However, conditions adversely affecting lysosomal iron handling (or oxidant stress) can contribute to a variety of acute and chronic diseases. These considerations make normal and abnormal lysosomal handling of iron central to the understanding and, perhaps, therapy of a wide range of diseases

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“…Apoptosis occurs via a mitochondrial-dependent intrinsic pathway or a death receptor-mediated extrinsic pathway [23][24][25] . The intrinsic pathway of apoptosis is regulated by members of the Bcl-2 family, which is composed of proapoptotic members (ie, Bax, and Bad) and anti-apoptotic members (ie, Bcl-2 and Bcl-X L ).…”

Section: Discussionmentioning

confidence: 99%

“…Curcumin-induced apoptosis is mediated via caspase activation in NTera-2 cells Caspases are cell-death proteases that play a significant role in both the initiation and execution of apoptotic programs in diverse species [20,21] . Caspase assays revealed that curcumin induced caspase 9, 8, and 3 activation in a dose-dependent manner, and the levels of cleaved PARP also increased ( Figure 3B).…”

Section: Curcumin Treatment Inhibited the Proliferation Of Testicularmentioning

confidence: 99%

“…NTera-2 cells were cultured in 12-well plates (1×10 5 cells/well) covered with the appropriate slips for 12 h. Then, curcumin (5,10,15,20, and 25 μmol/L) was added to the fresh medium. Twenty-four hours later, the cells were washed with cold PBS and fixed www.nature.com/aps Zhou C et al Acta Pharmacologica Sinica npg with 4% paraformaldehyde.…”

Section: Tunel Assaymentioning

confidence: 99%

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Curcumin inhibits AP-2γ-induced apoptosis in the human malignant testicular germ cells in vitro

Zhou

Zhao

et al. 2013

Acta Pharmacol Sin

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Aim: To investigate the effects of curcumin on proliferation and apoptosis in testicular cancer cells in vitro and to investigate its molecular mechanisms of action. Methods: NTera-2 human malignant testicular germ cell line and F9 mouse teratocarcinoma stem cell line were used. The anti-proliferative effect was examined using MTT and colony formation assays. Hoechst 33258 staining, TUNEL and Annexin V-FITC/PI staining assays were used to analyze cell apoptosis. Protein expression was examined with Western blot analysis and immunocytochemical staining. Results: Curcumin (5, 10 and 15 μmol/L) inhibited the viability of NTera-2 cells in dose-and time-dependent manners. Curcumin significantly inhibited the colony formation in both NTera-2 and F9 cells. Curcumin dose-dependently induced apoptosis of NTera-2 cells by reducing FasL expression and Bcl-2-to-Bax ratio, and activating caspase-9, -8 and -3. Furthermore, curcumin dose-dependently reduced the expression of AP transcription factor AP-2γ in NTera-2 cells, whereas the pretreatment with the proteasome inhibitor MG132 blocked both the curcumin-induced reduction of AP-2γ and antiproliferative effect. Curcumin inhibited ErbB2 expression, and decreased the phosphorylation of Akt and ERK in NTera-2 cells. Conclusion: Curcumin induces apoptosis and inhibits proliferation in NTera-2 cells via the inhibition of AP-2γ-mediated downstream cell survival signaling pathways.

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Cysteine Cathepsins Trigger Caspase-dependent Cell Death through Cleavage of Bid and Antiapoptotic Bcl-2 Homologues

Cited by 338 publications

References 65 publications

Autophagy of metallothioneins prevents TNF-induced oxidative stress and toxicity in hepatoma cells

Autophagy of metallothioneins prevents TNF-induced oxidative stress and toxicity in hepatoma cells

The role of lysosomes in iron metabolism and recycling

Curcumin inhibits AP-2γ-induced apoptosis in the human malignant testicular germ cells in vitro

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