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

M. Granato, V. Lacconi, M. Peddis, L. V. Lotti, L. D. Renzo, R. Gonnella, R. Santarelli, P. Trivedi, L. Frati, G. D'Orazi, A. Faggioni, M. Cirone

Research output: Contribution to journalArticlepeer-review

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-l, on primary effusion lymphoma (PEL) cell viability was analyzed. PES treatment induced a dose-and timedependent 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 apoptosisactivating 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.

Original languageEnglish
Article numbere730
JournalCell Death and Disease
Volume4
Issue number7
DOIs
Publication statusPublished - Jul 2013

Keywords

  • Bid
  • Cathepsin D
  • Dendritic cells
  • PEL
  • PES

ASJC Scopus subject areas

  • Cell Biology
  • Immunology
  • Cancer Research
  • Cellular and Molecular Neuroscience

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