journal contribution
posted on 2023-03-31, 21:13 authored by Jiu-Yang Zhang, Pei-Pei Zhang, Wen-Ping Zhou, Jia-Yu Yu, Zhi-Hua Yao, Jun-Feng Chu, Shu-Na Yao, Cheng Wang, Waseem Lone, Qing-Xin Xia, Jie Ma, Shu-Jun Yang, Kang-Dong Liu, Zi-Gang Dong, Yong-Jun Guo, Lynette M. Smith, Timothy W. McKeithan, Wing C. Chan, Javeed Iqbal, Yan-Yan Liu Figure S3 shows the survival curve of patients treated by CHOP regimen.There was survival indifference between patients with distinct CACNA1C expression in the setting of CHOP treatment (p>0.05).
Funding
National Natural Science Foundation of China
NCI
Lymphoma Research Foundation
Leukemia and Lymphoma Society
UNMC
National Center for Research Resources
National Institute for General Medical Science
History
ARTICLE ABSTRACT
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 in vitro and in vivo studies using cell lines and patient-derived xenograft mouse models.
A significant inverse correlation was observed between CACNA1C expression and RCHOP resistance in two independent DLBCL cohorts, and CACNA1C 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 CACNA1C expression was directly regulated by miR-363 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.
