Abstract
Abstract The thiazole-derivative 3-methylcyclopentilidene-[4-(4′-chlorophenyl)thiazol-2-yl]hydrazone (CPTH6) is a Gcn5 and pCAF histone acetyltransferases inhibitor that induces apoptosis and cell cycle arrest in human leukemia cells. The aim of this study was to evaluate whether CPTH6-induced apoptosis is associated with other cell death mechanisms, such as autophagy. Herein, we show that CPTH6 interferes with autophagic flux in several human tumor cell lines of different origin. CPTH6 treatment increases microtubule-associated protein 1 light chain 3-II (LC3-II) levels and induces the appearance of typical LC3-II- associated autophagosomal puncta in a time- and dose-dependent manner. Moreover, this compound decreases the expression of autophagy promoting proteins beclin1, Atg5 and Atg12. Strikingly, combined treatment of CPTH6 with bafilomycin A1, a proton ATPase inhibitor, demonstrates that CPTH6 reduces autophagosomes turnover, through an impairment of their degradation pathway, rather than enhancing autophagosomes formation. According to these results, CPTH6 treatment enhances p62/SQSTM1 protein levels in several tumor cell lines, indicating a blockage of autophagic cargo degradation. CPTH6 also reduces the phosphorylation of several components of transduction signalling pathways, such as Akt, 4E-BP1 and eIF4E, ERK1/2 and GSK-3α/β while it activates p38 MAPK pathway. In vivo CPTH6 exposure does not produce any adverse effects on health in mice as monitored by diet consumption, body-weight loss, postural and behavioral changes. Most importantly, CPTH6 exerts antitumoral effect on U937 human leukemia xenografts. These findings demonstrate that CPTH6 induces apoptosis and interferes with autophagic flux in human cancer cells, supporting further exploration of CPTH6 and related molecules as potential anticancer agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-82. doi:1538-7445.AM2012-LB-82
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