V-ATPase is a candidate therapeutic target for Ewing sarcoma

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1832

Article

Avnet, Sofia¹  Di Pompo, Gemma¹  Lemma, Silvia¹  Salerno, Manuela¹  Perut, Francesca¹  Bonuccelli, Gloria¹  Granchi, Donatella¹  Zini, Nicoletta²  Baldini, Nicola^1,3 

[1] Ist Ortoped Rizzoli, Lab Orthopaed Pathophysiol & Regenerat Med, I-40136 Bologna, Italy

[2] Ist Ortoped Rizzoli, Unit Bologna, IGM CNR, I-40136 Bologna, Italy

[3] Univ Bologna, Dept Biomed & Neuromotor Sci, I-40136 Bologna, Italy

关键词: Ewing sarcoma;    Glycolysis;    Extracellular acidification;    V-ATPase;   

DOI  :  10.1016/j.bbadis.2013.04.003

来源: Elsevier

【 摘 要 】

Suppression of oxidative phosphorylation combined with enhanced aerobic glycolysis and the resulting increased generation of protons are common features of several types of cancer. An efficient mechanism to escape cell death resulting from intracellular acidification is proton pump activation. In Ewing sarcoma (ES), although the tumor-associated chimeric gene EWS-FLI1 is known to induce the accumulation of hypoxia-induced transcription factor HIF-1 alpha, derangements in metabolic pathways have been neglected so far as candidate pathogenetic mechanisms. In this paper, we observed that ES cells simultaneously activate mitochondrial respiration and high levels of glycolysis. Moreover, although the most effective detoxification mechanism of proton intracellular storage is lysosomal compartmentalization, ES cells show a poorly represented lysosomal compartment, but a high sensitivity to the anti-lysosomal agent bafilomycin A1, targeting the V-ATPase proton pump. We therefore investigated the role of V-ATPase in the acidification activity of ES cells. ES cells with the highest GAPDH and V-ATPase expression also showed the highest acidification rate. Moreover, the localization of V-ATPase was both on the vacuolar and the plasma membrane of all ES cell lines. The acidic extracellular pH that we reproduced in vitro promoted high invasion ability and clonogenic efficiency. Finally, targeting V-ATPase with siRNA and omeprazole treatments, we obtained a significant selective reduction of tumor cell number. In summary, glycolytic activity and activation of V-ATPase are crucial mechanisms of survival of ES cells and can be considered as promising selective targets for the treatment of this tumor. (C) 2013 Elsevier B.V. All rights reserved.

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