Selective inhibition of PED protein expression sensitizes B-cell chronic lymphocytic leukaemia cells to TRAIL-induced apoptosis.
B-cell chronic lymphocytic leukaemia (B-CLL) cells fail to undergo apoptosis. The mechanism underlying this resistance to cell death is still largely unknown. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) effectively kills tumour cells but not normal cells, and thus represents an attractive tool for the treatment of cancer. Unfortunately, lymphocytes from B-CLL patients are resistant to TRAIL-mediated apoptosis. Thus, we aimed to study the involvement of PED, a DED-family member with a broad antiapoptotic action, in this resistance. We demonstrate that B lymphocytes obtained from patients with B-CLL express high levels of PED. Treatment of B-CLL cells with specific PED antisense oligonucleotides, a protein synthesis inhibitor or HDAC inhibitors, induced a significant downregulation of PED and sensitized these cells to TRAIL-induced cell death. These findings suggest a direct involvement of PED in resistance to TRAIL-induced apoptosis in B-CLL. It also identifies this DED-family member as a potential therapeutic target for this form of leukaemia.
Garofalo
Michela
M
Department of Cellular and Molecular Biology and Pathology, University of Naples Federico II, Via Pansini 5, 80131-Naples, Italy.
Romano
Giulia
G
Quintavalle
Cristina
C
Romano
Maria Fiammetta
MF
Chiurazzi
Federico
F
Zanca
Ciro
C
Condorelli
Gerolama
G
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004791:Enzyme Inhibitors; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism*; D008297:Male; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010750:Phosphoproteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*
D051017:Apoptosis Regulatory Proteins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D016376:Oligonucleotides, Antisense; C092039:PEA15 protein, human; D010750:Phosphoproteins; D012333:RNA, Messenger; D053221:TNF-Related Apoptosis-Inducing Ligand