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, indicates 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, suggesting 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. Phosphorylation of p38 MAP kinase is also observed after CPTH6 exposure, and the selective p38 inhibitor, SB 203580, blocks CPTH6-induced LC3-II conversion. 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.
Modulation of Autophagic Flux by CPTH6, a Gcn5/pCAF Histone Acetyltransferase Inhibitor With Antitumoral Activity / D., Trisciuoglio; Ragazzoni, Ylenia; M., Desideri; C., Gabellini; Nescatelli, Riccardo; Carradori, Simone; Secci, Daniela; D., Del Bufalo. - In: EUROPEAN JOURNAL OF CANCER. - ISSN 0959-8049. - STAMPA. - 48:(2012), pp. S232-S232. (Intervento presentato al convegno 22nd Biennial Congress of the EUROPEAN ASSOCIATION FOR CANCER RESEARCH.From Basic Research to Personalised Cancer Treatment tenutosi a Barcellona nel 7-10/07/2012).
Modulation of Autophagic Flux by CPTH6, a Gcn5/pCAF Histone Acetyltransferase Inhibitor With Antitumoral Activity
RAGAZZONI, YLENIA;NESCATELLI, RICCARDO;CARRADORI, Simone;SECCI, DANIELA;
2012
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, indicates 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, suggesting 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. Phosphorylation of p38 MAP kinase is also observed after CPTH6 exposure, and the selective p38 inhibitor, SB 203580, blocks CPTH6-induced LC3-II conversion. 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
