HSP70 inhibition by 2-phenylethynesulfonamide induces lysosomal cathepsin D release and immunogenic cell death in primary effusion lymphoma

• Published in: Cell death & disease 2013-07, Vol.4 (7), p.e730-e730
• Main Authors: Granato, M, Lacconi, V, Peddis, M, Lotti, L V, Di Renzo, L, Gonnella, R, Santarelli, R, Trivedi, P, Frati, L, D’Orazi, G, Faggioni, A, Cirone, M
• Format: Article
• Language: English
• Subjects: 631/250/2504/133; 631/45/612/1241; 631/80/82; 692/699/67/1990/291/1621/1915; Active Transport, Cell Nucleus; Antibodies; Antineoplastic Agents - pharmacology; Apoptosis Inducing Factor - metabolism; Autophagy; BH3 Interacting Domain Death Agonist Protein - metabolism; Biochemistry; Biomedical and Life Sciences; Cathepsin D - antagonists & inhibitors; Cathepsin D - metabolism; Cell Biology; Cell Culture; Cell Line, Tumor; Cell Survival - drug effects; Dendritic Cells - drug effects; Dendritic Cells - immunology; Drug Screening Assays, Antitumor; HSP70 Heat-Shock Proteins - antagonists & inhibitors; HSP70 Heat-Shock Proteins - metabolism; Humans; Immunology; Life Sciences; Lymphoma, Primary Effusion; Lysosomes - drug effects; Lysosomes - enzymology; Mitochondrial Membranes - drug effects; Mitochondrial Membranes - metabolism; Original; original-article; Pepstatins - pharmacology; Permeability; Protease Inhibitors - pharmacology; Sulfonamides - pharmacology
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2013.263

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.