Role of Calcium Signaling in GA101-Induced Cell Death in Malignant Human B Cells
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 o...
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| Format: | Article |
| Language: | English |
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MDPI AG
2019-03-01
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| Series: | Cancers |
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| Online Access: | http://www.mdpi.com/2072-6694/11/3/291 |
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| author | Simon Latour Marion Zanese Valérie Le Morvan Anne-Marie Vacher Nelly Menard Fontanet Bijou Francoise Durrieu Pierre Soubeyran Ariel Savina Pierre Vacher Laurence Bresson-Bepoldin |
| author_facet | Simon Latour Marion Zanese Valérie Le Morvan Anne-Marie Vacher Nelly Menard Fontanet Bijou Francoise Durrieu Pierre Soubeyran Ariel Savina Pierre Vacher Laurence Bresson-Bepoldin |
| author_sort | Simon Latour |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T09:05:05Z |
| format | Article |
| id | doaj.art-ca5d5b6a86c9477d8afc0af1f39d51e0 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T09:05:05Z |
| publishDate | 2019-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-ca5d5b6a86c9477d8afc0af1f39d51e02023-09-02T15:23:49ZengMDPI AGCancers2072-66942019-03-0111329110.3390/cancers11030291cancers11030291Role of Calcium Signaling in GA101-Induced Cell Death in Malignant Human B CellsSimon Latour0Marion Zanese1Valérie Le Morvan2Anne-Marie Vacher3Nelly Menard4Fontanet Bijou5Francoise Durrieu6Pierre Soubeyran7Ariel Savina8Pierre Vacher9Laurence Bresson-Bepoldin10Institut Bergonié, Comprehensive Cancer Centre, F-33000 Bordeaux, FranceInstitut Bergonié, Comprehensive Cancer Centre, F-33000 Bordeaux, FranceInstitut Bergonié, Comprehensive Cancer Centre, F-33000 Bordeaux, FranceInstitut Bergonié, Comprehensive Cancer Centre, F-33000 Bordeaux, FranceInstitut Bergonié, Comprehensive Cancer Centre, F-33000 Bordeaux, FranceInstitut Bergonié, Comprehensive Cancer Centre, F-33000 Bordeaux, FranceInstitut Bergonié, Comprehensive Cancer Centre, F-33000 Bordeaux, FranceInstitut Bergonié, Comprehensive Cancer Centre, F-33000 Bordeaux, FranceInstitut Roche, 92100 Boulogne-Billancourt, FranceInstitut Bergonié, Comprehensive Cancer Centre, F-33000 Bordeaux, FranceInstitut Bergonié, Comprehensive Cancer Centre, F-33000 Bordeaux, FranceGA101/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.http://www.mdpi.com/2072-6694/11/3/291anti-CD20GA101calcium signalingmalignant B cellscell death |
| spellingShingle | Simon Latour Marion Zanese Valérie Le Morvan Anne-Marie Vacher Nelly Menard Fontanet Bijou Francoise Durrieu Pierre Soubeyran Ariel Savina Pierre Vacher Laurence Bresson-Bepoldin Role of Calcium Signaling in GA101-Induced Cell Death in Malignant Human B Cells Cancers anti-CD20 GA101 calcium signaling malignant B cells cell death |
| title | Role of Calcium Signaling in GA101-Induced Cell Death in Malignant Human B Cells |
| title_full | Role of Calcium Signaling in GA101-Induced Cell Death in Malignant Human B Cells |
| title_fullStr | Role of Calcium Signaling in GA101-Induced Cell Death in Malignant Human B Cells |
| title_full_unstemmed | Role of Calcium Signaling in GA101-Induced Cell Death in Malignant Human B Cells |
| title_short | Role of Calcium Signaling in GA101-Induced Cell Death in Malignant Human B Cells |
| title_sort | role of calcium signaling in ga101 induced cell death in malignant human b cells |
| topic | anti-CD20 GA101 calcium signaling malignant B cells cell death |
| url | http://www.mdpi.com/2072-6694/11/3/291 |
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