Hydrogen Peroxide-Mediated Cytosolic Acidification Is a Signal for Mitochondrial Translocation of Bax during Drug-Induced Apoptosis of Tumor Cells

Ahmad, Kashif; Iskandar, Kartini; Hirpara, Jayshree L.; Clément, Marie‐Véronique; Pervaiz, Shazib

doi:10.1158/0008-5472.can-04-0648

Cited by 126 publications

(108 citation statements)

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“…However, other data seem to suggest that activation of the PI3K-Akt pathway could generate other reactive species like nitric oxide and superoxide, which would further enhance the downstream effects of this pathway (33)(34)(35)(36). These are intriguing findings, given our previous reports highlighting the role of intracellular redox status in the sensitivity of cancer cells to death stimuli (37)(38)(39)(40)(41)(42)(43)(44). We showed that a slight pro-oxidant intracellular milieu, invariably associated with the transformed phenotype, favors cell survival either by its positive effect on cell proliferation (45) or by impeding death execution pathway(s) (41,43,44,46).…”

Section: Introductionmentioning

confidence: 77%

LY294002 and LY303511 Sensitize Tumor Cells to Drug-Induced Apoptosis via Intracellular Hydrogen Peroxide Production Independent of the Phosphoinositide 3-Kinase-Akt Pathway

Poh

Pervaiz²

2005

Cancer Research

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The phosphoinositide 3-kinase (PI3K)-Akt pathway is constitutively active in many tumors, and inhibitors of this prosurvival network, such as LY294002, have been shown to sensitize tumor cells to death stimuli. Here, we report a novel, PI3K-independent mechanism of LY-mediated sensitization of LNCaP prostate carcinoma cells to drug-induced apoptosis. Preincubation of tumor cells to LY294002 or its inactive analogue LY303511 resulted in a significant increase in intracellular hydrogen peroxide (H 2 O 2 ) production and enhanced sensitivity to nonapoptotic concentrations of the chemotherapeutic agent vincristine. The critical role of intracellular H 2 O 2 in LY-induced death sensitization is corroborated by transient transfection of cells with a vector containing human catalase gene. Indeed, overexpression of catalase significantly blocked the amplifying effect of LY pretreatment on caspase-2 and caspase-3 activation and cell death triggered by vincristine. Furthermore, the inability of wortmannin, another inhibitor of PI3K, to induce an increase in H 2 O 2 production at doses that effectively blocked Akt phosphorylation provides strong evidence to unlink inhibition of PI3K from intracellular H 2 O 2 production. These data strongly support death-sensitizing effect of LY compounds independent of the PI3K pathway and underscore the critical role of H 2 O 2 in creating a permissive intracellular milieu for efficient drug-induced execution of tumor cells. (Cancer Res 2005; 65(14): 6264-74)

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Section: Introductionmentioning

confidence: 77%

LY294002 and LY303511 Sensitize Tumor Cells to Drug-Induced Apoptosis via Intracellular Hydrogen Peroxide Production Independent of the Phosphoinositide 3-Kinase-Akt Pathway

Poh

Pervaiz²

2005

Cancer Research

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“…One common cellular response to a number of oxidative and metabolic challenges is a reduction of intracellular pH (pHi) [36,39,40]; this is likely an early and essential event during apoptosis and/or necrosis [41]. Mechanisms proposed for cytosolic acidification include: dysregulation of ion transport [42]; proton leakage from acidic organelles [43]; and hydrolysis of high energy nucleotides [44].…”

Section: Oxidative and Metabolic Stresses Induce Cytosolic Acidificationmentioning

confidence: 99%

Mitochondrial translocation of α-synuclein is promoted by intracellular acidification

Cole

DiEuliis

Leo

et al. 2008

Experimental Cell Research

180

164

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Mitochondrial dysfunction plays a central role in the selective vulnerability of dopaminergic neurons in Parkinson's disease (PD) and is influenced by both environmental and genetic factors. Expression of the PD protein α-synuclein or its familial mutants often sensitizes neurons to oxidative stress and to damage by mitochondrial toxins. This effect is thought to be indirect, since little evidence physically linking α-synuclein to mitochondria has been reported. Here, we show that the distribution of α-synuclein within neuronal and non-neuronal cells is dependent on intracellular pH. Cytosolic acidification induces translocation of α-synuclein from the cytosol onto the surface of mitochondria. Translocation occurs rapidly under artificially-induced low pH conditions and as a result of pH changes during oxidative or metabolic stress. Binding is likely facilitated by low pH-induced exposure of the mitochondria-specific lipid cardiolipin. These results imply a direct role for α-synuclein in mitochondrial physiology, especially under pathological conditions, and in principle, link α-synuclein to other PD genes in regulating mitochondrial homeostasis.

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“…27,28 This view is, however, questioned by studies demonstrating that resveratrol-mediated apoptosis is, at least in part, independent on Bax but mostly related to the Bax/Bak inactivation. 29 p53 modulation.…”

confidence: 99%

Resveratrol: From Basic Science to the Clinic

Cucciolla¹,

Borriello²,

Oliva³

et al. 2007

Cell Cycle

162

102

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Plants produce an extraordinary array of low molecular mass natural products endowed with biological activity. Among these molecules, resveratrol (3,5,4'-trihydroxystilbene) has been identified as an inhibitor of carcinogenesis with a pleiotropic mode of action. Extensive literature on its anticancer activity, performed in cellular models, suggests a potential antiproliferative and apoptogenic use of the stilbene. Similarly, studies on implanted cancers and chemical-induced tumors confirm a potential chemotherapeutical interest of the compound. Moreover, recent intriguing studies have demonstrated, in mice, that the negative effects (insulin resistance and hyperglycemia) of a high-fat diet might be prevented by resveratrol treatment. Despite these promising observations, only few clinical trials have been performed on the compound due to the scarce interest of pharmaceutical industry. We suggest that resveratrol might be considered an interesting anticancer compound in association with more specific target-oriented drugs.

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Hydrogen Peroxide-Mediated Cytosolic Acidification Is a Signal for Mitochondrial Translocation of Bax during Drug-Induced Apoptosis of Tumor Cells

Cited by 126 publications

References 50 publications

LY294002 and LY303511 Sensitize Tumor Cells to Drug-Induced Apoptosis via Intracellular Hydrogen Peroxide Production Independent of the Phosphoinositide 3-Kinase-Akt Pathway

LY294002 and LY303511 Sensitize Tumor Cells to Drug-Induced Apoptosis via Intracellular Hydrogen Peroxide Production Independent of the Phosphoinositide 3-Kinase-Akt Pathway

Mitochondrial translocation of α-synuclein is promoted by intracellular acidification

Resveratrol: From Basic Science to the Clinic

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