Shikonin as a WT1 Inhibitor Promotes Promyeloid Leukemia Cell Differentiation
This study aims to observe the differentiating effect of shikonin on Wilms’ tumor 1 (WT1)-positive HL-60 cells and investigate the fate of the differentiated leukemia cells. WT1 overexpression unaffected cell viability but promoted resistance to H<sub>2</sub>O<sub>2</sub>-ind...
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| Format: | Article |
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MDPI AG
2022-11-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/27/23/8264 |
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| author | Zhenzhen Guo Luyao Sun Haojie Xia Shibin Tian Mengyue Liu Jiejie Hou Jiahuan Li Haihong Lin Gangjun Du |
| author_facet | Zhenzhen Guo Luyao Sun Haojie Xia Shibin Tian Mengyue Liu Jiejie Hou Jiahuan Li Haihong Lin Gangjun Du |
| author_sort | Zhenzhen Guo |
| collection | DOAJ |
| description | This study aims to observe the differentiating effect of shikonin on Wilms’ tumor 1 (WT1)-positive HL-60 cells and investigate the fate of the differentiated leukemia cells. WT1 overexpression unaffected cell viability but promoted resistance to H<sub>2</sub>O<sub>2</sub>-induced DNA injury and cell apoptosis. The binding of shikonin to the WT1 protein was confirmed by molecular docking and drug affinity reaction target stability (DARTS). Shikonin at the non-cytotoxic concentration could decrease the WT1 protein and simultaneously reduced the CD34 protein and increased the CD11b protein in a dose-dependent manner in normal HL-60 cells but not in WT1-overexpressed HL-60 cells. Shikonin unaffected HL-60 cell viability in 48 h. However, it lasted for 10 days; could attenuate cell proliferation, mitochondrial membrane potential (MMP), and self-renewal; prevent the cell cycle; promote cell apoptosis. In a mouse leukemia model, shikonin could decrease the WT1 protein to prevent leukemia development in a dose-dependent manner. In this study, we also confirmed preliminarily the protein–protein interactions between WT1 and CD34 in molecular docking and CO-IP assay. Our results suggest that: 1. shikonin can down-regulate the WT1 protein level for leukemia differentiation therapy, and 2. the interaction between WT1 and CD34 proteins may be responsible for granulocyte/monocyte immaturity in HL-60 cells. |
| first_indexed | 2024-03-09T17:39:50Z |
| format | Article |
| id | doaj.art-953620c1f77a420da73b746e314c0a8d |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T17:39:50Z |
| publishDate | 2022-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-953620c1f77a420da73b746e314c0a8d2023-11-24T11:39:24ZengMDPI AGMolecules1420-30492022-11-012723826410.3390/molecules27238264Shikonin as a WT1 Inhibitor Promotes Promyeloid Leukemia Cell DifferentiationZhenzhen Guo0Luyao Sun1Haojie Xia2Shibin Tian3Mengyue Liu4Jiejie Hou5Jiahuan Li6Haihong Lin7Gangjun Du8Henan Province Engineering Research Center of High Value Utilization to Natural Medical Resource in Yellow River Basin, Pharmaceutical College, Henan University, Kaifeng 475004, ChinaHenan Province Engineering Research Center of High Value Utilization to Natural Medical Resource in Yellow River Basin, Pharmaceutical College, Henan University, Kaifeng 475004, ChinaHenan Province Engineering Research Center of High Value Utilization to Natural Medical Resource in Yellow River Basin, Pharmaceutical College, Henan University, Kaifeng 475004, ChinaHenan Province Engineering Research Center of High Value Utilization to Natural Medical Resource in Yellow River Basin, Pharmaceutical College, Henan University, Kaifeng 475004, ChinaHenan Province Engineering Research Center of High Value Utilization to Natural Medical Resource in Yellow River Basin, Pharmaceutical College, Henan University, Kaifeng 475004, ChinaHenan Province Engineering Research Center of High Value Utilization to Natural Medical Resource in Yellow River Basin, Pharmaceutical College, Henan University, Kaifeng 475004, ChinaHenan Province Engineering Research Center of High Value Utilization to Natural Medical Resource in Yellow River Basin, Pharmaceutical College, Henan University, Kaifeng 475004, ChinaHenan Province Engineering Research Center of High Value Utilization to Natural Medical Resource in Yellow River Basin, Pharmaceutical College, Henan University, Kaifeng 475004, ChinaHenan Province Engineering Research Center of High Value Utilization to Natural Medical Resource in Yellow River Basin, Pharmaceutical College, Henan University, Kaifeng 475004, ChinaThis study aims to observe the differentiating effect of shikonin on Wilms’ tumor 1 (WT1)-positive HL-60 cells and investigate the fate of the differentiated leukemia cells. WT1 overexpression unaffected cell viability but promoted resistance to H<sub>2</sub>O<sub>2</sub>-induced DNA injury and cell apoptosis. The binding of shikonin to the WT1 protein was confirmed by molecular docking and drug affinity reaction target stability (DARTS). Shikonin at the non-cytotoxic concentration could decrease the WT1 protein and simultaneously reduced the CD34 protein and increased the CD11b protein in a dose-dependent manner in normal HL-60 cells but not in WT1-overexpressed HL-60 cells. Shikonin unaffected HL-60 cell viability in 48 h. However, it lasted for 10 days; could attenuate cell proliferation, mitochondrial membrane potential (MMP), and self-renewal; prevent the cell cycle; promote cell apoptosis. In a mouse leukemia model, shikonin could decrease the WT1 protein to prevent leukemia development in a dose-dependent manner. In this study, we also confirmed preliminarily the protein–protein interactions between WT1 and CD34 in molecular docking and CO-IP assay. Our results suggest that: 1. shikonin can down-regulate the WT1 protein level for leukemia differentiation therapy, and 2. the interaction between WT1 and CD34 proteins may be responsible for granulocyte/monocyte immaturity in HL-60 cells.https://www.mdpi.com/1420-3049/27/23/8264shikoninleukemiaWilms’ tumor gene 1 (WT1)CD34cell differentiation |
| spellingShingle | Zhenzhen Guo Luyao Sun Haojie Xia Shibin Tian Mengyue Liu Jiejie Hou Jiahuan Li Haihong Lin Gangjun Du Shikonin as a WT1 Inhibitor Promotes Promyeloid Leukemia Cell Differentiation Molecules shikonin leukemia Wilms’ tumor gene 1 (WT1) CD34 cell differentiation |
| title | Shikonin as a WT1 Inhibitor Promotes Promyeloid Leukemia Cell Differentiation |
| title_full | Shikonin as a WT1 Inhibitor Promotes Promyeloid Leukemia Cell Differentiation |
| title_fullStr | Shikonin as a WT1 Inhibitor Promotes Promyeloid Leukemia Cell Differentiation |
| title_full_unstemmed | Shikonin as a WT1 Inhibitor Promotes Promyeloid Leukemia Cell Differentiation |
| title_short | Shikonin as a WT1 Inhibitor Promotes Promyeloid Leukemia Cell Differentiation |
| title_sort | shikonin as a wt1 inhibitor promotes promyeloid leukemia cell differentiation |
| topic | shikonin leukemia Wilms’ tumor gene 1 (WT1) CD34 cell differentiation |
| url | https://www.mdpi.com/1420-3049/27/23/8264 |
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