Role of Calcium Signaling in GA101-Induced Cell Death in Malignant Human B Cells
AbstractGA101/obinutuzumab is a novel type II anti-CD20 monoclonal antibody (mAb), which is more effective than rituximab (RTX) in preclinical and clinical studies when used in combination with chemotherapy. Ca2+ signaling was shown to play a role in RTX-induced cell death. This report concerns the effect of GA101 on Ca2+ signaling and its involvement in the direct cell death induced by GA101. We reveal that GA101 triggered an intracellular Ca2+ increase by mobilizing intracellular Ca2+ stores and activating Orai1-dependent Ca2+ influx in non-Hodgkin lymphoma cell lines and primary B-Cell Chronic Lymphocytic Leukemia (B-CLL) cells. According to the cell type, Ca2+ was mobilized from two distinct intracellular compartments. In Raji, BL2, and B-CLL cells, GA101 induced a Ca2+ release from lysosomes, leading to the subsequent lysosomal membrane permeabilization and cell death. Inhibition of this calcium signaling reduced GA101-induced cell death in these cells. In SU-DHL-4 cells, GA101 mobilized Ca2+ from the endoplasmic reticulum (ER). Inhibition of ER replenishment, by blocking Orai1-dependent Ca2+ influx, led to an ER stress and unfolded protein response (UPR) which sensitized these cells to GA101-induced cell death. These results revealed the central role of Ca2+ signaling in GA101’s action mechanism, which may contribute to designing new rational drug combinations improving its clinical efficacy. View Full-Text
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Latour, S.; Zanese, M.; Le Morvan, V.; Vacher, A.-M.; Menard, N.; Bijou, F.; Durrieu, F.; Soubeyran, P.; Savina, A.; Vacher, P.; Bresson-Bepoldin, L. Role of Calcium Signaling in GA101-Induced Cell Death in Malignant Human B Cells. Cancers 2019, 11, 291.
Latour S, Zanese M, Le Morvan V, Vacher A-M, Menard N, Bijou F, Durrieu F, Soubeyran P, Savina A, Vacher P, Bresson-Bepoldin L. Role of Calcium Signaling in GA101-Induced Cell Death in Malignant Human B Cells. Cancers. 2019; 11(3):291.Chicago/Turabian Style
Latour, Simon; Zanese, Marion; Le Morvan, Valérie; Vacher, Anne-Marie; Menard, Nelly; Bijou, Fontanet; Durrieu, Francoise; Soubeyran, Pierre; Savina, Ariel; Vacher, Pierre; Bresson-Bepoldin, Laurence. 2019. "Role of Calcium Signaling in GA101-Induced Cell Death in Malignant Human B Cells." Cancers 11, no. 3: 291.
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