Center for Human Disease Genomics, Department of Immunology, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing, 100191, PR China; Key Laboratory of Medical Immunology, Ministry of Health, School of Basic Medical Science, Peking University, Beijing, 100191, PR China.
Department of Hematology and Lymphoma Research Center, Peking University, Third Hospital, Beijing, 100191, PR China.
Exp Cell Res. 2019 Dec 1;385(1):111623. doi: 10.1016/j.yexcr.2019.111623. Epub 2019 Sep 19.
Lymphoma is among the top 10 leading causes of cancer-related morbidity around the world in males, but currently, there is a lack of effective treatment strategies for this disease. Recently, we identified an alternatively spliced protein isoform, CMTM1-v5, which is significantly associated with tumor development and could serve as a potential therapeutic drug for lymphoma. Here, we showed that the overexpression of CMTM1-v5 in Raji cells or the addition of the CMTM1-v5 polypeptide to the cell culture medium induced apoptosis in vitro. During the in vivo experiments, most of the fluorescent CMTM1-v5 polypeptide converged within the tumor cells in Raji xenografts 24 h after treatment, and the injection of the polypeptide into the tail vein significantly extended survival in mice bearing Raji tumor cells. Mechanistically, the interaction between CMTM1-v5 and CAML (calcium-modulating cyclophilin ligand) negatively regulated the Ca response in the ER, inducing the activation of caspases and the release of cytochrome c in mitochondria and resulting in cell apoptosis. Thus, our study provides a proof-to-concept that supports the use of CMTM1-v5 to treat lymphoma.
淋巴瘤是全球男性癌症相关发病率的前 10 大原因之一，但目前针对这种疾病缺乏有效的治疗策略。最近，我们鉴定了一种剪接变异体蛋白 CMTM1-v5，它与肿瘤的发展显著相关，可作为治疗淋巴瘤的潜在药物。在这里，我们证明了 CMTM1-v5 在 Raji 细胞中的过表达或在细胞培养物中添加 CMTM1-v5 多肽可诱导体外细胞凋亡。在体内实验中，在注射后 24 小时内，荧光 CMTM1-v5 多肽大部分集中在 Raji 异种移植瘤的肿瘤细胞内，并且将该多肽注入尾静脉可显著延长携带 Raji 肿瘤细胞的小鼠的存活时间。在机制上，CMTM1-v5 与 CAML（钙调节环孢菌素配体）之间的相互作用负调控内质网中的钙反应，诱导半胱天冬酶的激活和线粒体中细胞色素 c 的释放，导致细胞凋亡。因此，我们的研究提供了一个概念验证，支持使用 CMTM1-v5 来治疗淋巴瘤。
