Chongqing City Key Lab of Translational Medical Research in Cognitive Development and Learning and Memory Disorders; Ministry of Education Key Laboratory of Child Development and Disorders; National Clinical Research Center for Child Health and Disorders (Chongqing); and Department of Neurology, Children's Hospital of Chongqing Medical University, 400014, Chongqing, China.
Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada.
Signal Transduct Target Ther. 2021 Feb 8;6(1):52. doi: 10.1038/s41392-020-00410-5.
Increased endogenous hydrogen sulfide (HS) level by cystathionine β-synthase (CBS) has been shown to closely relate tumorigenesis. HS promotes angiogenesis, stimulates bioenergy metabolism and inhibits selective phosphatases. However, the role of CBS and HS in chronic myeloid leukemia (CML) remains elusive. In this study, we found that CBS and HS levels were increased in the bone marrow mononuclear cells of pediatric CML patients, as well as in the CML-derived K562 cells and CBS expression levels were correlated with different disease phases. Inhibition of CBS reduced the proliferation of the CML primary bone marrow mononuclear cells and induced growth inhibition, apoptosis, cell cycle arrest, and migration suppression in K562 cells and tumor xenografts. The knockdown of CBS expression by shRNA and inhibiting CBS activity by AOAA decreased the endogenous HS levels, promoted mitochondrial-related apoptosis and inhibited the NF-κB-mediated gene expression. Our study suggests that inhibition of CBS induces cell apoptosis, as well as limits cell proliferation and migration, a potential target for the treatment of chronic myeloid leukemia.
内源性硫化氢（HS）水平的增加已被证明与肿瘤发生密切相关。HS 促进血管生成，刺激生物能量代谢并抑制选择性磷酸酶。然而，CBS 和 HS 在慢性髓性白血病（CML）中的作用仍不清楚。在这项研究中，我们发现儿科 CML 患者骨髓单个核细胞以及 CML 衍生的 K562 细胞中 CBS 和 HS 水平升高，并且 CBS 表达水平与不同的疾病阶段相关。CBS 的抑制减少了 CML 原代骨髓单个核细胞的增殖，并诱导 K562 细胞和肿瘤异种移植物中的生长抑制、凋亡、细胞周期停滞和迁移抑制。shRNA 下调 CBS 表达和 AOAA 抑制 CBS 活性降低了内源性 HS 水平，促进了与线粒体相关的凋亡并抑制了 NF-κB 介导的基因表达。我们的研究表明，CBS 的抑制诱导细胞凋亡，并限制细胞增殖和迁移，这可能成为治疗慢性髓性白血病的一个潜在靶点。
