TY - JOUR
T1 - HSP70 inhibition by 2-phenylethynesulfonamide induces lysosomal cathepsin D release and immunogenic cell death in primary effusion lymphoma
AU - Granato, M.
AU - Lacconi, V.
AU - Peddis, M.
AU - Lotti, L. V.
AU - Renzo, L. D.
AU - Gonnella, R.
AU - Santarelli, R.
AU - Trivedi, P.
AU - Frati, L.
AU - D'Orazi, G.
AU - Faggioni, A.
AU - Cirone, M.
PY - 2013/7
Y1 - 2013/7
N2 - 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.
AB - 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.
KW - Bid
KW - Cathepsin D
KW - Dendritic cells
KW - PEL
KW - PES
UR - http://www.scopus.com/inward/record.url?scp=84881080283&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84881080283&partnerID=8YFLogxK
U2 - 10.1038/cddis.2013.263
DO - 10.1038/cddis.2013.263
M3 - Article
C2 - 23868063
AN - SCOPUS:84881080283
VL - 4
JO - Cell Death and Disease
JF - Cell Death and Disease
SN - 2041-4889
IS - 7
M1 - e730
ER -