L-type cav 1.2 calcium channel-a-1C regulates response to rituximab in diffuse large B-cell lymphoma

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

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Purpose: 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. Experimental Design: 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. Results: 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. Conclusions: We identified the role of CACNA1C in rituximab resistance, and modulating its expression or activity may alter rituximab sensitivity in DLBCL.

Original languageEnglish (US)
Pages (from-to)4168-4178
Number of pages11
JournalClinical Cancer Research
Volume25
Issue number13
DOIs
StatePublished - 2019

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Zhang, J. Y., Zhang, P. P., Zhou, W. P., Yu, J. Y., Yao, Z. H., Chu, J. F., Yao, S. N., Wang, C., Lone, W., Xia, Q. X., Ma, J., Yang, S. J., Liu, K. D., Dong, Z. G., Guo, Y. J., Smith, L. M., McKeithan, T. W., Chan, W. C., Iqbal, J., & Liu, Y. Y. (2019). L-type cav 1.2 calcium channel-a-1C regulates response to rituximab in diffuse large B-cell lymphoma. Clinical Cancer Research, 25(13), 4168-4178. https://doi.org/10.1158/1078-0432.CCR-18-2146