Next Article in Journal
Role of Notch Signaling Pathway in Glioblastoma Pathogenesis
Next Article in Special Issue
The Volume-Regulated Anion Channel in Glioblastoma
Previous Article in Journal
Cancer-Associated Fibroblasts’ Functional Heterogeneity in Pancreatic Ductal Adenocarcinoma
Previous Article in Special Issue
Implication of Voltage-Gated Potassium Channels in Neoplastic Cell Proliferation
Article Menu
Issue 3 (March) cover image

Export Article

Open AccessArticle
Cancers 2019, 11(3), 291;

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

Institut Bergonié, Comprehensive Cancer Centre, F-33000 Bordeaux, France
Department of Life and Health Sciences, University of Bordeaux, F-33076 Bordeaux, France
INSERM, U1218 ACTION, F-33000 Bordeaux, France
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)
Full-Text   |   PDF [2595 KB, uploaded 1 March 2019]   |  


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

Graphical abstract

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).

Supplementary material


Share & Cite This Article

MDPI and ACS Style

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.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics



[Return to top]
Cancers EISSN 2072-6694 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top