Dual regulation of caspase activity by hydrogen peroxide: implications for apoptosis

Hampton, Mark B.; Orrenius, Sten

doi:10.1016/s0014-5793(97)01068-5

Cited by 618 publications

(424 citation statements)

References 20 publications

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“…This study and other studies have shown the redox modification of caspase activity through the use of oxidants such as peroxide 40 (and Figure 4), diamide 59 and the dithiocarbamate disulfides. 60 It is becoming evident that the cellular reducing environment maintained by endogenous antioxidants such as glutathione and thioredoxin 59 plays an important role in the ability of the caspases to execute the effector stages of the apoptotic program.…”

Section: Discussionsupporting

confidence: 63%

“…38 This, together with studies demonstrating the sensitivity of caspases to redox state alterations, 40 suggested that the inactivation of caspase-3 during retinal cell apoptosis may be due to oxidative modification. Figure 4A demonstrates the ability of peroxide to inactivate the caspase activity in a cytosolic extract from anti-Fas IgM treated Jurkat cells.…”

Section: Caspases Are Oxidatively Inactivated During Retinal Cell Deathmentioning

confidence: 99%

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Oxidative stress induces caspase-independent retinal apoptosis in vitro

2000

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Apoptosis is the mode of cell death in retinitis pigmentosa (RP), a heterogeneous group of retinal degenerations. The activation of the caspase proteases forms a pivotal step in the initiation and execution phase of apoptosis in many cells. Inhibition of caspases has been reported to prevent apoptosis in many model systems. However, we demonstrate the absence of caspase activation during retinal cell apoptosis in vitro which involves phosphatidylserine (PS) externalisation, DNA nicking and cell shrinkage. In addition, zVAD-fmk, DEVD-CHO and BD-fmk, inhibitors of the caspases, were unable to alter the characteristics or kinetics of apoptosis, implying that retinal cell death in vitro follows a caspase-independent pathway. We have previously demonstrated the ability of reactive oxygen species (ROS) to act as mediators of retinal cell apoptosis in vitro as well as the ability of antioxidants to prevent retinal cell apoptosis. Here we demonstrate the oxidative inactivation of caspases in this model of retinal apoptosis and provide evidence for an oxidative stress driven cell death pathway that does not involve caspase activity and which retains key features of apoptotic cell death. Furthermore, our data indicates that apoptotic events such as PS exposure, DNA nicking and cell shrinkage may occur independently of caspase activity. Cell Death and Differentiation (2000) 7, 282 ± 291.

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Section: Discussionsupporting

confidence: 63%

Section: Caspases Are Oxidatively Inactivated During Retinal Cell Deathmentioning

confidence: 99%

Oxidative stress induces caspase-independent retinal apoptosis in vitro

2000

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“…However, mounting evidence, including the results presented herein, is showing that tightly regulated ROS can subsequently regulate caspases, 21 phosphatases 19 and Ras itself. 18 Man-A caused a large induction ( 12-fold) of AEO 2 2 in WEHI-231 lymphoma cells, but much weaker responses were noted in the A20.2J lymphoma and in Du145, human prostate cancer cells.…”

Section: Discussionmentioning

confidence: 74%

“…An emerging body of evidence is revealing that ROS can mediate and regulate finely tuned biochemical responses. [17][18][19][20][21] Therefore, because the tumor cells underwent apoptosis, we explored the impact of Man-A-stimulated ROS on cellular caspase activation and the influence of ROS on the Ras/MEK/ERK and Ras/PI3K/Akt signaling systems, which are known to impart growth and survival advantages on tumor cells.For the first time, our data show that Man-A-stimulated ROS participate in caspase activation, the dephosphorylation of Akt, Raf, MEK and ERK, and specific cleavage of MEK and Akt, but not of ERK. Furthermore, Man-A deactivated Ras signaling effectors without inhibiting Ras activity.…”

mentioning

confidence: 99%

Reactive oxygen species‐dependent destruction of MEK and Akt in Manumycin stimulated death of lymphoid tumor and myeloma cell lines

Sears

Daino

Carey

2008

Intl Journal of Cancer

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Manumycin-A (Man-A) is a farnesyltransferase inhibitor (FTI), which was originally identified as an effective tumoricide against several cancers, especially ones harboring constitutively active Ras. However, it is becoming apparent that Man-A can stimulate tumor death independently of FTases. Antioxidant treatment blocked Man-A-stimulated DNA damage and reversed Man-Ainhibited tumor growth. However, the precise molecular details of how these reactive oxygen species (ROS) influence cell signaling modules are poorly understood. We examined how ROS may modulate death and survival pathways in a panel of tumor cells. Man-A treatment resulted in a massive induction of superoxide anion (AEO 2 2 ) only in Man-A-sensitive tumors. Within 1 hr, Man-A caused the ROS-dependent activation of caspases 9 and 3. In this time-frame, the Ras-Raf target, MEK, and the survival protein Akt were dephosphorylated in ROS-dependent fashions and then cleaved in ROS and caspase-dependent manners. Pretreatment with ROS scavengers blocked the adverse effects of Man-A, including the processing of caspases and the cleavage of MEK and Akt. These events were noted before any losses in Ras activity or changes in its maturation could be detected. Finally, transfection with cDNAs encoding the antioxidant enzymes catalase, superoxide dismutase and thioredoxin reductase inhibited superoxide induction and apoptosis. Together, our data suggest that the elimination of tumors by Man-A can be independent of the inhibiting of Ras. However, one universal feature observed is the generation of death-triggering intracellular oxidants that appear to directly participate in the select targeting of growth and survival proteins that then either augment or ensure tumor cell death. ' 2007 Wiley-Liss, Inc.Key words: Manumycin; farnesyltransferase inhibitor; MEK; Akt; reactive oxygen species; cleavage; caspase; Ras Ras is a small, 21 kDa, guanosine triphosphate (GTP)-binding protein, which controls numerous cellular functions including growth and proliferation as well as providing scaffolding for other signaling enzymes. Ras regulates the PI3K/Akt and PI3K/mTOR/ p70 S6K signaling modules, which drive cell proliferation, cell growth and survival. 1 Furthermore, the canonical Ras signaling network (Ras/Raf/MEK/ERK) regulates anabolism, induces growth-enhancing genes through transcription factors such as Elk-1 and it also suppresses the activities of proapoptotic proteins. 2 Hence, it is not surprising that 30% of known human tumors and 90% of pancreatic carcinomas, one of the most aggressive and morbid types of cancer, harbor mutated or dysfunctional Ras. [3][4][5] Together these features make Ras an attractive target for cancer therapy.Ras maturation requires the post-translational transfer of a farnesyl hydrocarbon group to its C-terminal cysteine in a process termed prenylation, 6-8 which is essential for the subsequent localization of Ras at the plasma membrane where receptor signals regulate its on and off state. 9 Because prenylation is also required for subsequen...

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“…At higher concentrations (4200 mM), H 2 O 2 inhibits the activation of caspases and rather induces necrosis. 30 H 2 O 2 also inhibits the activation of recombinant caspases suggesting that the caspase inhibitory effect is dependent on direct interference with caspase activity. 31 Therefore, it might well be that APIT produces levels of H 2 O 2 that damage the cell but prevent apoptosis by blocking caspase function.…”

Section: Discussionmentioning

confidence: 99%

Hydrogen peroxide produced by Aplysia ink toxin kills tumor cells independent of apoptosis via peroxiredoxin I sensitive pathways

et al. 2004

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Marine snails of the genus Aplysia possess numerous bioactive substances. We have purified a 60 kDa protein, APIT (Aplysia punctata ink toxin), from the defensive ink of A. punctata that triggers cell death with profound tumor specificity. Tumor cell death induced by APIT is independent of apoptosis but is characterized by the rapid loss of metabolic activity, membrane permeabilization, and shrinkage of nuclei. Proteome analysis of APIT-treated tumor cells indicated a modification of peroxiredoxin I, a cytoplasmic peroxidase involved in the detoxification of peroxides. Interestingly, knockdown of peroxiredoxin I expression by RNA interference sensitized cells for APIT-induced cell death. APIT induced the death of tumor cells via the enzymatic production of H 2 O 2 and catalase completely blocked APITs' activity. Our data suggest that H 2 O 2 induced stress and the modulation of peroxiredoxins might be a promising approach for tumor therapy.

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Dual regulation of caspase activity by hydrogen peroxide: implications for apoptosis

Cited by 618 publications

References 20 publications

Oxidative stress induces caspase-independent retinal apoptosis in vitro

Oxidative stress induces caspase-independent retinal apoptosis in vitro

Reactive oxygen species‐dependent destruction of MEK and Akt in Manumycin stimulated death of lymphoid tumor and myeloma cell lines

Hydrogen peroxide produced by Aplysia ink toxin kills tumor cells independent of apoptosis via peroxiredoxin I sensitive pathways

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