title: Type II anti-CD20 mAb-induced lysosome mediated cell death is mediated through a ceramide-dependent pathway.
abstract: In the past decade, monoclonal antibodies (mAbs) have revolutionized the treatment of non-Hodgkin lymphomas (NHLs). Although Fc-dependent mechanisms of mAb-mediated tumor clearance have been extensively studied, the ability of mAbs to directly evoke programmed cell death (PCD) and the underlying mechanisms involved remain unclear. It is well established that type II anti-CD20 mAb (Tositumomab) potently evoked PCD through a caspases-independent, lysosome-mediated process, which is related to homotypic adhesion (HA) in NHL cell lines. Herein, we reveal that the induction of ceramide generation by anti-CD20 mAbs directly correlates with their ability to induce PCD. The inhibition of ceramide abrogated Tositumomab-induced PCD indicating that ceramide is required for the execution of cell death. Further experimental results revealed that ceramide was generated downstream of mAb-induced HA and upstream of lysosome leakage. These findings provide further insights into a previously unrecognized role for ceramide generation in mediating PCD evoked by type II anti-CD20 mAbs in Burkitt's lymphoma cells. This newly characterized cell death pathway may potentially be exploited to eliminate malignant cells.
authors.affiliation: Department of Thoracic Surgery, General Hospital of Armed Police Forces, 69 Yongding Road, Beijing 100039, PR China.
authors.forename: Hua
authors.initials: H
authors.lastname: Ren
authors.affiliation: Department of Thoracic Surgery, General Hospital of Armed Police Forces, 69 Yongding Road, Beijing 100039, PR China. Electronic address: cwzhang@yeah.net.
authors.forename: Chengwei
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Thoracic Surgery, General Hospital of Armed Police Forces, 69 Yongding Road, Beijing 100039, PR China.
authors.forename: Liwei
authors.initials: L
authors.lastname: Su
authors.affiliation: Department of Thoracic Surgery, General Hospital of Armed Police Forces, 69 Yongding Road, Beijing 100039, PR China.
authors.forename: Xin
authors.initials: X
authors.lastname: Bi
authors.affiliation: Department of Thoracic Surgery, General Hospital of Armed Police Forces, 69 Yongding Road, Beijing 100039, PR China.
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Thoracic Surgery, General Hospital of Armed Police Forces, 69 Yongding Road, Beijing 100039, PR China.
authors.forename: Liang
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Thoracic Surgery, General Hospital of Armed Police Forces, 69 Yongding Road, Beijing 100039, PR China.
authors.forename: Bo
authors.initials: B
authors.lastname: Wu
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D018951:Antigens, CD20 / Q000276:immunology*; D000970:Antineoplastic Agents / Q000276:immunology / Q000494:pharmacology*; D002051:Burkitt Lymphoma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D020169:Caspases / Q000276:immunology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002518:Ceramides / Q000276:immunology*; D006801:Humans; D008247:Lysosomes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; D018951:Antigens, CD20; D000970:Antineoplastic Agents; D002518:Ceramides; D020169:Caspases
keywords: Burkitt's lymphoma; CD20; Ceramide; Homotypic adhesion; Lysosome leakage; Programmed cell death