L-Type Cav 1.2 Calcium Channel-α-1C Regulates Response to Rituximab in Diffuse Large B-Cell Lymphoma

• Published in: Clinical cancer research Vol. 25; no. 13; pp. 4168 - 4178
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States 01.07.2019
• Subjects: Animals; Antigens, CD20 - metabolism; Antineoplastic Agents, Immunological - pharmacology; Antineoplastic Agents, Immunological - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Apoptosis - genetics; Calcium Channels, L-Type - genetics; Calcium Channels, L-Type - metabolism; Cyclophosphamide - adverse effects; Cyclophosphamide - therapeutic use; Disease Models, Animal; Doxorubicin - adverse effects; Doxorubicin - therapeutic use; Drug Resistance, Neoplasm; Epigenesis, Genetic; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Lymphoma, Large B-Cell, Diffuse - diagnosis; Lymphoma, Large B-Cell, Diffuse - drug therapy; Lymphoma, Large B-Cell, Diffuse - genetics; Lymphoma, Large B-Cell, Diffuse - metabolism; Mice; Positron Emission Tomography Computed Tomography; Prednisone - adverse effects; Prednisone - therapeutic use; Rituximab - adverse effects; Rituximab - pharmacology; Rituximab - therapeutic use; Tomography, X-Ray Computed; Vincristine - adverse effects; Vincristine - therapeutic use; Xenograft Model Antitumor Assays
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-18-2146

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.