Distinct BTK inhibitors differentially induce apoptosis but similarly suppress chemotaxis and lipid accumulation in mantle cell lymphoma

BMC Cancer

Mingxia Shi¹  Jian Yu²  Zhuojun Liu²  Jia Liu²  Jing Zhang²  Lin Li²  Tianming Zhang²  Hao Jia³  Xiaofang Chen³  Shuo Zhang³  Shuhua Yue³  Yuanshi Xia³ 

[1] Department of Hematology, the First Affiliated Hospital of Kunming Medical University, Kunming, China;Interdisciplinary Institute of Cancer Diagnosis and Treatment, Beijing Advanced Innovation Center for Biomedical Engineering, Beihang University, Beihang University, 100083, Beijing, China;School of Biological Science and Medical Engineering, Beihang University, 100083, Beijing, China;School of Biological Science and Medical Engineering, Beihang University, 100083, Beijing, China;

关键词: Mantle cell lymphoma;    Ibrutinib;    Acalabrutinib;    Zanubrutinib;    Apoptosis;    Chemotaxis;    Lipid droplet accumulation;   

DOI  :  10.1186/s12885-021-08475-3

来源: Springer

【 摘 要 】

BackgroundThe more selective second-generation BTK inhibitors (BTKi) Acalabrutinib and Zanubrutinib and the first-generation BTKi Ibrutinib are highlighted by their clinical effectiveness in mantle cell lymphoma (MCL), however, similarities and differences of their biological and molecular effects on anti-survival of MCL cells induced by these BTKi with distinct binding selectivity against BTK remain largely unknown.MethodsAlamarBlue assays were performed to define cytotoxicity of BTKi against MCL cells, Jeko-1 and Mino. Cleaved PARP and caspase-3 levels were examined by immunoblot analysis to study BTKi-induced apoptotic effects. Biological effects of BTKi on MCL-cell chemotaxis and lipid droplet (LD) accumulation were examined in Jeko-1, Mino and primary MCL cells via Transwell and Stimulated Raman scattering imaging analysis respectively. Enzyme-linked immunoassays were used to determine CCL3 and CCL4 levels in MCL-cell culture supernatants. RNA-seq analyses identified BTKi targets which were validated by quantitative RT-PCR (qRT-PCR) and immunoblot analysis.ResultsAcalabrutinib and Zanubrutinib induced moderate apoptosis in Ibrutinib high-sensitive JeKo-1 cells and Ibrutinib low-sensitive Mino cells, which was accompanied by cleaved PARP and caspase-3. Such effects might be caused by the stronger ability of Ibrutinib to upregulate the expression of pro-apoptotic genes, such as HRK, GADD45A, and ATM, in JeKo-1 cells than in Mino cells, and the expression of such apoptotic genes was slightly changed by Acalabrutinib and Zanubrutinib in both JeKo-1 and Mino cells. Further, Acalabrutinib, Zanubrutinib and Ibrutinib reduced MCL-cell chemotaxis with similar efficiency, due to their similar abilities to downmodulate chemokines, such as CCL3 and CCL4. Also, these three BTKi similarly suppressed MCL-cell LD accumulation via downregulating lipogenic factors, DGAT2, SCD, ENPP2 and ACACA without significant differences.ConclusionBTKi demonstrated differential capacities to induce MCL-cell apoptosis due to their distinct capabilities to regulate the expression of apoptosis-related genes, and similar biological and molecular inhibitory effects on MCL-cell chemotaxis and LD accumulation.

【 授权许可】

CC BY