The role of PKC in X-ray-induced megakaryocyte apoptosis and thrombocytopenia

Fanbi Meng; Shuang Chen; Chunliang Liu; Muhammad Shoaib Khan; Yan Yan; Jun Wan; Yue Xia; Chenglin Sun; Mengnan Yang; Renping Hu; Kesheng Dai

doi:10.1016/j.bcmd.2023.102798

The role of PKC in X-ray-induced megakaryocyte apoptosis and thrombocytopenia

Blood Cells Mol Dis. 2024 Jan:104:102798. doi: 10.1016/j.bcmd.2023.102798. Epub 2023 Oct 4.

Authors

Affiliations

¹ State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Cyrus Tang Medical Institute, Soochow University, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Key Laboratory of Thrombosis and Hemostasis, Suzhou 215000, China.
² State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Cyrus Tang Medical Institute, Soochow University, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Key Laboratory of Thrombosis and Hemostasis, Suzhou 215000, China. Electronic address: kdai@suda.edu.cn.

PMID: 37813040
DOI: 10.1016/j.bcmd.2023.102798

Abstract

Thrombocytopenia is a critical complication after radiation therapy and exposure. Dysfunction of megakaryocyte development and platelet production are key pathophysiological stages in ionizing radiation (IR)-induced thrombocytopenia. Protein kinase C (PKC) plays an important role in regulating megakaryocyte development and platelet production. However, it remains unclear how PKC regulates IR-induced megakaryocyte apoptosis. In this study, we found that pretreatment of PKC pan-inhibitor Go6983 delayed IR-induced megakaryocyte apoptosis, and inhibited IR-induced mitochondrial membrane potential and ROS production in CMK cells. Moreover, suppressing PKC activation inhibited cleaved caspase3 expression and reduced p38 phosphorylation levels, and IR-induced PKC activation might be regulated by p53. In vivo experiments confirmed that Go6983 promoted platelet count recovery after 21 days of 3 Gy total body irradiation. Furthermore, Go6983 reduced megakaryocyte apoptosis, increased the number of megakaryocyte and polyploid formation in bone marrow, and improved the survival rate of 6 Gy total body irradiation. In conclusion, our results provided a potential therapeutic target for IR-induced thrombocytopenia.

Keywords: Apoptosis; Irradiation damage; Megakaryocyte; Platelet; Protein kinase C.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis
Blood Platelets
Humans
Megakaryocytes*
Protein Kinase C / metabolism
Protein Kinase C / therapeutic use
Thrombocytopenia* / etiology
Thrombopoiesis
X-Rays

Substances

2-(1-(3-dimethylaminopropyl)-5-methoxyindol-3-yl)-3-(1H-indol-3-yl)maleimide
Protein Kinase C