Ritanserin suppresses acute myeloid leukemia by inhibiting DGKα to downregulate phospholipase D and the Jak-Stat/MAPK pathway

Jinshui Tan; Mengya Zhong; Yanyan Hu; Guangchao Pan; Jingwei Yao; Yuanfang Tang; Hongpeng Duan; Yuelong Jiang; Weihang Shan; Jiaqi Lin; Yating Liu; Jiewen Huang; Huijian Zheng; Yong Zhou; Guo Fu; Zhifeng Li; Bing Xu; Jie Zha

doi:10.1007/s12672-023-00737-9

Ritanserin suppresses acute myeloid leukemia by inhibiting DGKα to downregulate phospholipase D and the Jak-Stat/MAPK pathway

Discov Oncol. 2023 Jul 1;14(1):118. doi: 10.1007/s12672-023-00737-9.

Authors

Jinshui Tan^#^{1

2}, Mengya Zhong^#^{1

2}, Yanyan Hu^#³, Guangchao Pan^{1

2}, Jingwei Yao^{1

2}, Yuanfang Tang^{1

2

3}, Hongpeng Duan^{1

2}, Yuelong Jiang^{1

2}, Weihang Shan^{1

2}, Jiaqi Lin^{1

2

3}, Yating Liu^{1

2}, Jiewen Huang^{1

2

4}, Huijian Zheng⁵, Yong Zhou^{1

2}, Guo Fu⁶, Zhifeng Li^{1

2}, Bing Xu^{7

8}, Jie Zha^{9

10}

Affiliations

¹ Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, Fujian, People's Republic of China.
² Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, No. 55, Shizhen Hai Road, Xiamen, 361003, Fujian, People's Republic of China.
³ State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Innovation Center for Cell Biology, Xiamen University, Xiamen, 361002, Fujian, China.
⁴ School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361002, Fujian, China.
⁵ The School of Clinical Medicine, Fujian Medical University, Fuzhou, 350122, Fujian, China.
⁶ State Key Laboratory of Cellular Stress Biology, School of Medicine, Innovation Center for Cell Biology, Xiamen University, Xiamen, 361002, Fujian, China.
⁷ Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, Fujian, People's Republic of China. xubing@xmu.edu.cn.
⁸ Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, No. 55, Shizhen Hai Road, Xiamen, 361003, Fujian, People's Republic of China. xubing@xmu.edu.cn.
⁹ Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, Fujian, People's Republic of China. zhajie@xmu.edu.cn.
¹⁰ Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, No. 55, Shizhen Hai Road, Xiamen, 361003, Fujian, People's Republic of China. zhajie@xmu.edu.cn.

^# Contributed equally.

Abstract

Refractory or relapsed (R/R) AML is the most challenging form of AML to treat. Due to frequent genetic mutations, therapy alternatives are limited. Here, we identified the role of ritanserin and its target DGKα in AML. Several AML cell lines and primary patient cells were treated with ritanserin and subjected to cell proliferation, apoptosis and gene analyses with CCK-8 assay, Annexin V/PI assay and Western blotting, respectively. We also evaluated the function of the ritanserin target diacylglycerol kinase alpha (DGKα) in AML by bioinformatics. In vitro experiments have revealed that ritanserin inhibits AML progression in a dose- and time-dependent manner, and it shows an anti-AML effect in xenograft mouse models. We further demonstrated that the expression of DGKα was elevated in AML and correlated with poor survival. Mechanistically, ritanserin negatively regulates SphK1 expression through PLD signaling, also inhibiting the Jak-Stat and MAPK signaling pathways via DGKα. These findings suggest that DGKα may be an available therapeutic target and provide effective preclinical evidence of ritanserin as a promising treatment for AML.

Keywords: DGKα; Jak-Stat; MAPK; R/R AML; Ritanserin.

Abstract

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