Novel targets for endoplasmic reticulum stress-induced apoptosis in B-CLL

• Published in: Blood 2010-10, Vol.116 (15), p.2713-2723
• Main Authors: Rosati, Emanuela, Sabatini, Rita, Rampino, Giuliana, De Falco, Filomena, Di Ianni, Mauro, Falzetti, Franca, Fettucciari, Katia, Bartoli, Andrea, Screpanti, Isabella, Marconi, Pierfrancesco
• Format: Article
• Language: English
• Subjects: Apoptosis - drug effects; Apoptosis - physiology; Biological and medical sciences; Caspases - metabolism; Down-Regulation; Endoplasmic Reticulum - drug effects; Endoplasmic Reticulum - metabolism; Gene Rearrangement, B-Lymphocyte; Heat-Shock Proteins - antagonists & inhibitors; Heat-Shock Proteins - genetics; Hematologic and hematopoietic diseases; Humans; In Vitro Techniques; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Leukemia, Lymphocytic, Chronic, B-Cell - metabolism; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Leukemia, Lymphocytic, Chronic, B-Cell - therapy; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Membrane Proteins - metabolism; Models, Biological; RNA, Small Interfering - genetics; Signal Transduction - drug effects; Stress, Physiological; Thapsigargin - pharmacology; Tunicamycin - pharmacology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2010-03-275628

A better understanding of apoptotic signaling in B-chronic lymphocytic leukemia (B-CLL) cells may help to define new therapeutic strategies. This study investigated endoplasmic reticulum (ER) stress signaling in spontaneous apoptosis of B-CLL cells and whether manipulating ER stress increases their apoptosis. Results show that a novel ER stress-triggered caspase cascade, initiated by caspase-4 and involving caspase-8 and -3, plays an important role in spontaneous B-CLL cell apoptosis. ER stress-induced apoptosis in B-CLL cells also involves CHOP/GADD153 up-regulation, increased JNK1/2 phosphorylation, and caspase-8–mediated cleavage of Bap31 to Bap20, known to propagate apoptotic signals from ER to mitochondria. In ex vivo B-CLL cells, some apoptotic events associated with mitochondrial pathway also occur, including mitochondrial cytochrome c release and caspase-9 processing. However, pharmacologic inhibition studies show that caspase-9 plays a minor role in B-CLL cell apoptosis. ER stress also triggers survival signals in B-CLL cells by increasing BiP/GRP78 expression. Manipulating ER signaling by siRNA down-regulation of BiP/GRP78 or treating B-CLL cells with 2 well-known ER stress-inducers, tunicamycin and thapsigargin, increases their apoptosis. Overall, our findings show that ER triggers an essential pathway for B-CLL cell apoptosis and suggest that genetic and pharmacologic manipulation of ER signaling could represent an important therapeutic strategy.