Effects of XPO1 Inhibitor KPT-8602 on Proliferation and Apoptosis in U937 cells
- VernacularTitle:XPO1抑制剂KPT-8602对U937细胞增殖和凋亡的影响
- Author:
Xiao-hui XIAO
1
;
Yi-qing LI
1
;
Ke-zhi HUANG
1
;
Shuang-feng XIE
1
;
Jie XIAO
1
;
Li-ping MA
1
;
Song-mei YIN
1
;
Da-nian NIE
1
Author Information
1. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation // Department of Hematology，Sun Yat-Sen Memorial Hospital，Sun Yat-Sen University，Guangzhou 510120，China
- Publication Type:Journal Article
- Keywords:
XPO1;
KPT-8602;
U937 cells;
cell cycle|apoptosis;
AKT
- From:
Journal of Sun Yat-sen University(Medical Sciences)
2019;40(1):37-45
- CountryChina
- Language:Chinese
-
Abstract:
【Objective】To explore the effects and the possible mechanism of KPT- 8602，a novel selective inhibitor of nuclear export protein （XPO1），on proliferation，cell cycle and apoptosis in human histiocytic lymphoma cell line U937 cells.【Methods】U937 cells were treated with different concentrations of KPT- 8602. Cell viability was assessed by CCK-8 assay. The cell cycle distribution and the apoptosis rate were analyzed by flow cytometry. The proteins expression of XPO1，p-AKT，AKT，Cleaved Caspase-3，p21 were determined by Western blot. Fluorescence microscope was used in observing the intracellular location of XPO1. 【Results】 KPT- 8602 inhibited the growth of U937 cells in a dose- dependent（P<0.001）and time- dependent manner（P<0.001），but normal PBMC were unaffected. 48 h after treatment with KPT-8602，a higher proportion of cells in G1 phase was observed（P<0.001）and the apoptosis rate increased（P=0.016）with drug concentration in U937 cells. XPO1 protein expression of U937 cells was significantly higher than normal PBMC（P=0.003）. 48 h after treatment with KPT- 8602，the protein expression of XPO1 decreased（P=0.011），p-AKT decreased（P=0.011），and Cleaved Caspase- 3 increased（P=0.009）. In addition，the protein expression of p21，the cargo protein of XPO1，increased in both the nuclei and the cytoplasm（P<0.05）after treatment with KPT- 8602. XPO1 decreased in both the nuclei and the cytoplasm under the fluorescence microscope after treatment with KPT- 8602.【Conclusion】KPT- 8602 can inhibit the proliferation of U937 cells，block the cell cycle at G1 phase，and induce cell apoptosis，which may partially be attributed to the down-regulation of XPO1 and inhibition of PI3K/AKT signaling.
