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Cancers 2019, 11(3), 291; https://doi.org/10.3390/cancers11030291

Role of Calcium Signaling in GA101-Induced Cell Death in Malignant Human B Cells

1
Institut Bergonié, Comprehensive Cancer Centre, F-33000 Bordeaux, France
2
Department of Life and Health Sciences, University of Bordeaux, F-33076 Bordeaux, France
3
INSERM, U1218 ACTION, F-33000 Bordeaux, France
4
Institut Roche, 92100 Boulogne-Billancourt, France
*
Authors to whom correspondence should be addressed.
Received: 11 January 2019 / Revised: 15 February 2019 / Accepted: 22 February 2019 / Published: 1 March 2019
(This article belongs to the Special Issue Ion Channels in Cancer)
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Abstract

GA101/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
Keywords: anti-CD20; GA101; calcium signaling; malignant B cells; cell death anti-CD20; GA101; calcium signaling; malignant B cells; cell death
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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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.

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