Proton pump inhibitors (PPI) target tumour acidic pH and have an antineoplastic effect in melanoma. The PPI esomeprazole (ESOM) kills melanoma cells through a caspase-dependent pathway involving cytosolic acidification and alkalinization of tumour pH. In this paper, we further investigated the mechanisms of ESOM-induced cell death in melanoma. ESOM rapidly induced accumulation of reactive oxygen species (ROS) through mitochondrial dysfunctions and involvement of NADPH oxidase. The ROS scavenger N-acetyl-L-cysteine (NAC) and inhibition of NADPH oxidase significantly reduced ESOM-induced cell death, consistent with inhibition of cytosolic acidification. Autophagy, a cellular catabolic pathway leading to lysosomal degradation and recycling of proteins and organelles, represents a defence mechanism in cancer cells under metabolic stress. ESOM induced the early accumulation of autophagosomes, at the same time reducing the autophagic flux, as observed by WB analysis of LC3-II accumulation and by fluorescence microscopy. Moreover, ESOM treatment decreased mammalian target of rapamycin signalling, as reduced phosphorylation of p70-S6K and 4-EBP1 was observed. Inhibition of autophagy by knockdown of Atg5 and Beclin-1 expression significantly increased ESOM cytotoxicity, suggesting a protective role for autophagy in ESOM-treated cells. The data presented suggest that autophagy represents an adaptive survival mechanism to overcome drug-induced cellular stress and cytotoxicity, including alteration of pH homeostasis mediated by proton pump inhibition.

Marino, M., Fais, S., Djavaheri Mergny, M., Villa, A., Meschini, S., Lozupone, F., et al. (2010). Proton pump inhibition induces autophagy as a survival mechanism following oxidative stress in human melanoma cells. CELL DEATH & DISEASE, 1(10) [10.1038/cddis.2010.67].

Proton pump inhibition induces autophagy as a survival mechanism following oxidative stress in human melanoma cells

VILLA, ANTONELLO;
2010

Abstract

Proton pump inhibitors (PPI) target tumour acidic pH and have an antineoplastic effect in melanoma. The PPI esomeprazole (ESOM) kills melanoma cells through a caspase-dependent pathway involving cytosolic acidification and alkalinization of tumour pH. In this paper, we further investigated the mechanisms of ESOM-induced cell death in melanoma. ESOM rapidly induced accumulation of reactive oxygen species (ROS) through mitochondrial dysfunctions and involvement of NADPH oxidase. The ROS scavenger N-acetyl-L-cysteine (NAC) and inhibition of NADPH oxidase significantly reduced ESOM-induced cell death, consistent with inhibition of cytosolic acidification. Autophagy, a cellular catabolic pathway leading to lysosomal degradation and recycling of proteins and organelles, represents a defence mechanism in cancer cells under metabolic stress. ESOM induced the early accumulation of autophagosomes, at the same time reducing the autophagic flux, as observed by WB analysis of LC3-II accumulation and by fluorescence microscopy. Moreover, ESOM treatment decreased mammalian target of rapamycin signalling, as reduced phosphorylation of p70-S6K and 4-EBP1 was observed. Inhibition of autophagy by knockdown of Atg5 and Beclin-1 expression significantly increased ESOM cytotoxicity, suggesting a protective role for autophagy in ESOM-treated cells. The data presented suggest that autophagy represents an adaptive survival mechanism to overcome drug-induced cellular stress and cytotoxicity, including alteration of pH homeostasis mediated by proton pump inhibition.
Articolo in rivista - Articolo scientifico
TOR Serine-Threonine Kinases; Reactive Oxygen Species; Proton Pump Inhibitors; Ribosomal Protein S6 Kinases, 70-kDa; Oxidative Stress; Phosphoproteins; Autophagy; Membrane Proteins; Apoptosis Regulatory Proteins; Humans; Cell Line, Tumor; Melanoma; Antineoplastic Agents; NADPH Oxidase; Adaptor Proteins, Signal Transducing; Hydrogen-Ion Concentration; Microtubule-Associated Proteins; Signal Transduction; Omeprazole; Phosphorylation; Acetylcysteine;
English
2010
1
10
e87
none
Marino, M., Fais, S., Djavaheri Mergny, M., Villa, A., Meschini, S., Lozupone, F., et al. (2010). Proton pump inhibition induces autophagy as a survival mechanism following oxidative stress in human melanoma cells. CELL DEATH & DISEASE, 1(10) [10.1038/cddis.2010.67].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/39058
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