2. Academic Validation
  3. MORTALIN-Ca2+ axis drives innate rituximab resistance in diffuse large B-cell lymphoma

MORTALIN-Ca2+ axis drives innate rituximab resistance in diffuse large B-cell lymphoma

  • Cancer Lett. 2022 Jul 1;537:215678. doi: 10.1016/j.canlet.2022.215678.
Qi Sun 1,  Ying Ye 2,  Ailing Gui 1,  Xiaoting Sun 3,  Sisi Xie 1,  Yuhang Zhan 1,  Ruibo Chen 1,  Yichen Yan 1,  Juan Gu 4,  Shi Qiu 1,  Wen Liu 1,  Ji Zuo 5,  Qunling Zhang 6,  Ling Yang 7
Affiliations

Affiliations

  • 1 Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China.
  • 2 Department of Oral Implantology, School and Hospital of Stomatology, Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China.
  • 3 Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China; Department of Microbiology, Tumor and Cell Biology, Biomedicum, Karolinska Institute, Stockholm, Sweden.
  • 4 Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA; Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY, USA.
  • 5 Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China. Electronic address: jzuo@shmu.edu.cn.
  • 6 Department of Lymphoma, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. Electronic address: zhangqunling@fudan.edu.cn.
  • 7 Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China. Electronic address: yangling@fudan.edu.cn.
PMID: 35447282 DOI: 10.1016/j.canlet.2022.215678
Abstract

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin's lymphoma, with the combination of rituximab and chemotherapy being the standard treatment for it. Although rituximab monotherapy has a remarkable response rate, drug resistance with unclear mechanisms and lack of effective second-line therapy limit the survival benefits of patients with lymphoma. Here, we report that MORTALIN is highly expressed and correlates with resistance to rituximab-based therapy and poor survival in patients with DLBCL. Mechanistically, gain- and loss-of-function experiments revealed that the voltage-dependent anion channel 1-binding protein, MORTALIN, regulated CA2+ release from the endoplasmic reticulum through mitochondria-associated membrane, facilitating AP1-mediated cell proliferation and YY-1-mediated downregulation of FAS in DLBCL cells. These dual mechanisms contribute to rituximab resistance. In mouse models, genetic depletion of MORTALIN markedly increased the antitumor activity of rituximab. We shed mechanistic LIGHT on MORTALIN-Ca2+-CaMKII-AP1-mediated proliferation and MORTALIN-Ca2+-CaMKII-inhibited death receptor in DLBCL, leading to rituximab resistance, and propose MORTALIN as a novel target for the treatment of DLBCL.

Keywords

Calcium signaling; Drug resistance; Lymphoma; MORTALIN; Mitochondria-associated membranes.

Figures
Products