Zhang Jiu-Yang, Zhang Pei-Pei, Zhou Wen-Ping, Yu Jia-Yu, Yao Zhi-Hua, Chu Jun-Feng, Yao Shu-Na, Wang Cheng, Lone Waseem, Xia Qing-Xin, Ma Jie, Yang Shu-Jun, Liu Kang-Dong, Dong Zi-Gang, Guo Yong-Jun, Smith Lynette M, McKeithan Timothy W, Chan Wing C, Iqbal Javeed, Liu Yan-Yan
Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, Henan, China.
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska.
Clin Cancer Res. 2019 Jul 1;25(13):4168-4178. doi: 10.1158/1078-0432.CCR-18-2146. Epub 2019 Mar 1.
One third of patients with diffuse large B-cell lymphoma (DLBCL) succumb to the disease partly due to rituximab resistance. Rituximab-induced calcium flux is an important inducer of apoptotic cell death, and we investigated the potential role of calcium channels in rituximab resistance.
The distinctive expression of calcium channel members was compared between patients sensitive and resistant to rituximab, cyclophosphamide, vincristine, doxorubicin, prednisone (RCHOP) regimen. The observation was further validated through mechanistic and studies using cell lines and patient-derived xenograft mouse models.
A significant inverse correlation was observed between expression and RCHOP resistance in two independent DLBCL cohorts, and expression was an independent prognostic factor for RCHOP resistance after adjusting for International Prognostic Index, cell-of-origin classification, and MYC/BCL2 double expression. Loss of CACNA1C expression reduced rituximab-induced apoptosis and tumor shrinkage. We further demonstrated direct interaction of CACNA1C with CD20 and its role in CD20 stabilization. Functional modulators of L-type calcium channel showed expected alteration in rituximab-induced apoptosis and tumor suppression. Furthermore, we demonstrated that expression was directly regulated by whose high expression is associated with worse prognosis in DLBCL.
We identified the role of CACNA1C in rituximab resistance, and modulating its expression or activity may alter rituximab sensitivity in DLBCL.
三分之一的弥漫性大B细胞淋巴瘤（DLBCL）患者死于该疾病，部分原因是对利妥昔单抗耐药。利妥昔单抗诱导的钙内流是凋亡性细胞死亡的重要诱导因素，我们研究了钙通道在利妥昔单抗耐药中的潜在作用。
比较了对利妥昔单抗、环磷酰胺、长春新碱、多柔比星、泼尼松（RCHOP）方案敏感和耐药的患者之间钙通道成员的差异表达。通过使用细胞系和患者来源的异种移植小鼠模型进行机制研究进一步验证了该观察结果。
在两个独立的DLBCL队列中，观察到[某种钙通道成员]表达与RCHOP耐药之间存在显著的负相关，并且在调整国际预后指数、起源细胞分类和MYC/BCL2双表达后，[该钙通道成员]表达是RCHOP耐药的独立预后因素。CACNA1C表达缺失减少了利妥昔单抗诱导的细胞凋亡和肿瘤缩小。我们进一步证明了CACNA1C与CD20的直接相互作用及其在CD20稳定中的作用。L型钙通道的功能调节剂在利妥昔单抗诱导的细胞凋亡和肿瘤抑制中显示出预期的改变。此外，我们证明[该钙通道成员]表达直接受[另一种物质]调节，其高表达与DLBCL中较差的预后相关。
我们确定了CACNA1C在利妥昔单抗耐药中的作用，调节其表达或活性可能会改变DLBCL对利妥昔单抗的敏感性。
