title: Nutritional stress and arginine auxotrophy confer high sensitivity to chloroquine toxicity in mesothelioma cells.
abstract: The correlation between cell 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, which are still scarcely defined. In this study, we investigated the effects of CQ on growth, death, and autophagic activity of malignant mesothelioma 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). Furthermore, overexpression of ASS in these cells reduced their sensitivity to CQ toxicity. Based on these results, the assessment of ASS expression in malignant mesothelioma tissues may allow the identification of subgroups of tumors with an increased sensitivity to the toxic effects of this drug.
authors.affiliation: Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Italy.
authors.forename: Sonia
authors.initials: S
authors.lastname: Battisti
authors.forename: Davide
authors.initials: D
authors.lastname: Valente
authors.forename: Loredana
authors.initials: L
authors.lastname: Albonici
authors.forename: Roberto
authors.initials: R
authors.lastname: Bei
authors.forename: Andrea
authors.initials: A
authors.lastname: Modesti
authors.forename: Camilla
authors.initials: C
authors.lastname: Palumbo
mesh_terms: D001120:Arginine / Q000378:metabolism* / Q000494:pharmacology; D001124:Argininosuccinate Synthase / Q000235:genetics / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002738:Chloroquine / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D008654:Mesothelioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013312:Stress, Physiological; D059016:Tumor Microenvironment
chemical_list: D002738:Chloroquine; D001120:Arginine; D001124:Argininosuccinate Synthase