Document Detail


Nutritional Stress and Arginine Auxotrophy Confer High Sensitivity to Chloroquine Toxicity in Mesothelioma Cells.
MedLine Citation:
PMID:  22074703     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
The correlation between cells' sensitivity to autophagy inhibitors such as chloroquine (CQ) and the expression/activity of molecules involved in the control and execution of autophagy is well documented. However, tumor cells with comparable autophagic potentials may display variable degrees of autophagy addiction due to the differential expression of molecular determinants still scarcely defined. In this study we investigated the effects of CQ on growth, death and autophagic activity of malignant mesothelioma (MM) cell lines cultured in standard versus nutritional stress conditions partially mimicking those found in the tumor microenvironment. We report that in each cell line the toxic effects of CQ were amplified by nutritional stress and paralleled by autophagy inhibition. Still, the cell lines displayed different levels of sensitivity to CQ toxicity which did not correlate with their relative degrees of constitutive and nutritional stress-induced autophagy nor with the relative magnitude of the autophagy inhibition induced by the drug. Thus, we tested the hypothesis that the cell lines' sensitivity to CQ was related to their variable dependence on recycling of intracellular constituents by autophagy. In fact, the cell line with the highest sensitivity to the toxic effects of CQ was auxotrophic for arginine due to the deficient expression of the enzyme argininosuccinate synthetase (ASS). Further, overexpression of ASS in these cells reduced their sensitivity to CQ toxicity. Based on these results, the assessment of ASS expression in MM tissues may allow to identify subgroups of tumors with an increased sensitivity to the toxic effects of this drug.
Authors:
Sonia Battisti; Davide Valente; Loredana Albonici; Roberto Bei; Andrea Modesti; Camilla Palumbo
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-11-10
Journal Detail:
Title:  American journal of respiratory cell and molecular biology     Volume:  -     ISSN:  1535-4989     ISO Abbreviation:  -     Publication Date:  2011 Nov 
Date Detail:
Created Date:  2011-11-14     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8917225     Medline TA:  Am J Respir Cell Mol Biol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Rome, Italy.
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