title: HSP70 inhibition by 2-phenylethynesulfonamide induces lysosomal cathepsin D release and immunogenic cell death in primary effusion lymphoma.
abstract: Heat-shock protein (HSP) 70 is aberrantly expressed in different malignancies and has a cancer-specific cell-protective effect. As such, it has emerged as a promising target for anticancer therapy. In this study, the effect of the HSP70-specific inhibitor (PES), also Pifitrin-μ, on primary effusion lymphoma (PEL) cell viability was analyzed. PES treatment induced a dose- and time-dependent cytotoxic effect in BC3 and BCBL1 PEL cells by inducing lysosome membrane permeabilization, relocation of cathepsin D in the cytosol, Bid cleavage, mitochondrial depolarization with release and nuclear translocation of apoptosis-activating factor. The PES-induced cell death in PEL cells was characterized by the appearance of Annexin-V/propidium iodide double-positive cells from the early times of treatment, indicating the occurrence of an additional type of cell death other than apoptosis, which, accordingly, was not efficiently prevented by the pan-caspase inhibitor Z-VAD-fmk. Conversely, PES-induced cell death was robustly reduced by pepstatin A, which inhibits Bid and caspase 8 processing. In addition, PES was responsible for a block of the autophagic process in PEL cells. Finally, we found that PES-induced cell death has immunogenic potential being able to induce dendritic cell activation.
authors.affiliation: Department of Experimental Medicine and Pathology, Istituto Pasteur Fondazione Cenci Bolognetti, La Sapienza University, Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Granato
authors.forename: V
authors.initials: V
authors.lastname: Lacconi
authors.forename: M
authors.initials: M
authors.lastname: Peddis
authors.forename: L V
authors.initials: LV
authors.lastname: Lotti
authors.forename: L
authors.initials: L
authors.lastname: Di Renzo
authors.forename: L D
authors.initials: LD
authors.lastname: Renzo
authors.forename: R
authors.initials: R
authors.lastname: Gonnella
authors.forename: R
authors.initials: R
authors.lastname: Santarelli
authors.forename: P
authors.initials: P
authors.lastname: Trivedi
authors.forename: L
authors.initials: L
authors.lastname: Frati
authors.forename: G
authors.initials: G
authors.lastname: D'Orazi
authors.forename: A
authors.initials: A
authors.lastname: Faggioni
authors.forename: M
authors.initials: M
authors.lastname: Cirone
mesh_terms: D021581:Active Transport, Cell Nucleus; D000970:Antineoplastic Agents / Q000494:pharmacology*; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D001343:Autophagy; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D002402:Cathepsin D / Q000037:antagonists & inhibitors / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D004354:Drug Screening Assays, Antitumor; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D054685:Lymphoma, Primary Effusion; D008247:Lysosomes / Q000187:drug effects* / Q000201:enzymology; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism; D010436:Pepstatins / Q000494:pharmacology; D010539:Permeability; D011480:Protease Inhibitors / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: C545747:2-phenylacetylenesulfonamide; C494829:AIFM1 protein, human; D000970:Antineoplastic Agents; D051033:Apoptosis Inducing Factor; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D018840:HSP70 Heat-Shock Proteins; D010436:Pepstatins; D011480:Protease Inhibitors; D013449:Sulfonamides; D002402:Cathepsin D; C031375:pepstatin