Combating rituximab resistance by inducing ceramide/lysosome-involved cell death through initiation of CD20-TNFR1 co-localization
Combating rituximab resistance by inducing ceramide/lysosome-involved cell death through initiation of CD20-TNFR1 co-localization
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DOI：
10.1080/2162402x.2016.1143995
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发表时间：
2016-02
期刊：
影响因子：
7.2
通讯作者：
Fan Zhang;Jun-lan Yang;Huafei Li;Moyan Liu;Jie Zhang;Li-chao Zhao;Lingxiong Wang;R. Linghu;F. Feng;Xudong Gao;B. Dong;Xiaohan Liu;Jian Zi;Wei-jing Zhang;Yi Hu;Jingkun Pan;L. Tian;Yazuo Hu;Zhitao Han;Honghong Zhang;Xiaoning Wang;Lei Zhao
中科院分区：
文献类型：
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作者：
Fan Zhang;Jun-lan Yang;Huafei Li;Moyan Liu;Jie Zhang;Li-chao Zhao;Lingxiong Wang;R. Linghu;F. Feng;Xudong Gao;B. Dong;Xiaohan Liu;Jian Zi;Wei-jing Zhang;Yi Hu;Jingkun Pan;L. Tian;Yazuo Hu;Zhitao Han;Honghong Zhang;Xiaoning Wang;Lei Zhao
尽管CD 20抗体利妥昔单抗在免疫治疗中取得了成功，但获得性耐药是B细胞恶性肿瘤成功治疗的主要障碍之一。迫切需要加强努力，消除癌症治疗中的耐药性。越来越多的证据表明，溶酶体可能通过使癌细胞对死亡途径敏感而形成癌细胞的“阿喀琉斯之踵”。在这里，我们发现了一个重要的作用，CD 20在启动神经酰胺/溶酶体膜透化（LMP）介导的细胞死亡，表明共定位的CD 20-TNFR 1后，II型CD 20抗体连接可以刺激从头神经酰胺合成酶的神经酰胺合成，从而诱导显着的溶酶体透化（LMP）和溶酶体介导的细胞死亡。进一步的研究表明，由CD 20抗体诱导的有效溶酶体介导的细胞死亡对利妥昔单抗敏感性和耐药性（RR）淋巴瘤都表现出深刻的杀伤作用。此外，通过引入点突变对利妥昔单抗进行工程改造，使其能够在利妥昔单抗难治性患者的RR淋巴瘤和原发性B细胞恶性肿瘤中诱导有效的神经酰胺/LMP介导的细胞死亡，这表明了对抗利妥昔单抗耐药性的潜在临床应用。
ABSTRACT Despite the success of CD20 antibody rituximab in immunotherapy, acquired resistance is one of the prime obstacles for the successful treatment of B-cell malignancies. There is an urgent need to intensify efforts against resistance in cancer treatment. Growing evidence indicated that lysosomes may form an “Achilles heel” for cancer cells by sensitizing them to death pathways. Here, we uncover an important role of CD20 in initiation of ceramide/lysosomal membrane permeabilization (LMP)-mediated cell death, showing that colocalization of CD20-TNFR1 after type II CD20 antibody ligation can stimulate de novo ceramide synthesis by ceramide synthase and consequently induce remarkable lysosomal permeabilization (LMP) and lysosome-mediated cell death. Further studies show that the potent lysosome-mediated cell death induced by CD20 antibodies exhibits a profound killing effect against both rituximab-sensitive and -resistant (RR) lymphoma. Furthermore, engineering of rituximab by introducing a point mutation endows it with the ability to induce potent ceramide/LMP-mediated cell death in both RR lymphoma and primary B-cell malignancies from patients with rituximab-refractory, suggesting the potential clinical application to combat rituximab resistance.