Anticancer Activity of Pyrimethamine via Ubiquitin Mediated Degradation of AIMP2-DX2
While aminoacyl-tRNA synthetase-interacting multifunctional protein 2 (AIMP2) is a tumor suppressor, its exon 2-depleted splice variant (AIMP2-DX2 or shortly DX2) is highly expressed in human lung cancer, and the ratio of DX2 to AIMP2 increases according to the progression of lung cancer. In this st...
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MDPI AG
2020-06-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/25/12/2763 |
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| author | Dae Gyu Kim Chul Min Park Srigouri Huddar Semi Lim Sunghoon Kim Sunkyung Lee |
| author_facet | Dae Gyu Kim Chul Min Park Srigouri Huddar Semi Lim Sunghoon Kim Sunkyung Lee |
| author_sort | Dae Gyu Kim |
| collection | DOAJ |
| description | While aminoacyl-tRNA synthetase-interacting multifunctional protein 2 (AIMP2) is a tumor suppressor, its exon 2-depleted splice variant (AIMP2-DX2 or shortly DX2) is highly expressed in human lung cancer, and the ratio of DX2 to AIMP2 increases according to the progression of lung cancer. In this study, pyrimethamine inhibited the level of DX2 (IC<sub>50</sub> = 0.73 µM) in A549 cells expressing nanoluciferase-tagged DX2. In a panel of 5 lung cancer cell lines with various DX2 levels, pyrimethamine most potently suppressed the growth of H460 cells, which express high levels of DX2 (GI<sub>50</sub> = 0.01 µM). An immunoblot assay in H460 cells showed that pyrimethamine decreased the DX2 level dose-dependently but did not affect the AIMP2 level. Further experiments confirmed that pyrimethamine resulted in ubiquitination-mediated DX2 degradation. In an in vivo mouse xenograft assay using H460 cells, intraperitoneal administration of pyrimethamine significantly reduced the tumor size and weight, comparable with the effects of taxol, without affecting body weight. Analysis of tumor tissue showed a considerably high concentration of pyrimethamine with a decreased levels of DX2. These results suggest that pyrimethamine, currently used as anti-parasite drug, could be repurposed to treat lung cancer patients expressing high level of DX2. |
| first_indexed | 2024-03-10T19:09:48Z |
| format | Article |
| id | doaj.art-0c7881a8254548de942a17e123be1779 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T19:09:48Z |
| publishDate | 2020-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-0c7881a8254548de942a17e123be17792023-11-20T03:53:14ZengMDPI AGMolecules1420-30492020-06-012512276310.3390/molecules25122763Anticancer Activity of Pyrimethamine via Ubiquitin Mediated Degradation of AIMP2-DX2Dae Gyu Kim0Chul Min Park1Srigouri Huddar2Semi Lim3Sunghoon Kim4Sunkyung Lee5Medicinal Bioconvergence Research Center, College of Pharmacy and College of Medicine, Gangnam Severance Hospital, Yonsei University, Incheon 21983, KoreaCenter for Convergent Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon 34114, KoreaDrug Information research Center, Korea Research Institute of Chemical Technology, Daejeon 34114, KoreaMedicinal Bioconvergence Research Center, College of Pharmacy and College of Medicine, Gangnam Severance Hospital, Yonsei University, Incheon 21983, KoreaMedicinal Bioconvergence Research Center, College of Pharmacy and College of Medicine, Gangnam Severance Hospital, Yonsei University, Incheon 21983, KoreaDrug Information research Center, Korea Research Institute of Chemical Technology, Daejeon 34114, KoreaWhile aminoacyl-tRNA synthetase-interacting multifunctional protein 2 (AIMP2) is a tumor suppressor, its exon 2-depleted splice variant (AIMP2-DX2 or shortly DX2) is highly expressed in human lung cancer, and the ratio of DX2 to AIMP2 increases according to the progression of lung cancer. In this study, pyrimethamine inhibited the level of DX2 (IC<sub>50</sub> = 0.73 µM) in A549 cells expressing nanoluciferase-tagged DX2. In a panel of 5 lung cancer cell lines with various DX2 levels, pyrimethamine most potently suppressed the growth of H460 cells, which express high levels of DX2 (GI<sub>50</sub> = 0.01 µM). An immunoblot assay in H460 cells showed that pyrimethamine decreased the DX2 level dose-dependently but did not affect the AIMP2 level. Further experiments confirmed that pyrimethamine resulted in ubiquitination-mediated DX2 degradation. In an in vivo mouse xenograft assay using H460 cells, intraperitoneal administration of pyrimethamine significantly reduced the tumor size and weight, comparable with the effects of taxol, without affecting body weight. Analysis of tumor tissue showed a considerably high concentration of pyrimethamine with a decreased levels of DX2. These results suggest that pyrimethamine, currently used as anti-parasite drug, could be repurposed to treat lung cancer patients expressing high level of DX2.https://www.mdpi.com/1420-3049/25/12/2763pyrimethamineAIMP2-DX2ubiquitinationanticancerdrug repositioning |
| spellingShingle | Dae Gyu Kim Chul Min Park Srigouri Huddar Semi Lim Sunghoon Kim Sunkyung Lee Anticancer Activity of Pyrimethamine via Ubiquitin Mediated Degradation of AIMP2-DX2 Molecules pyrimethamine AIMP2-DX2 ubiquitination anticancer drug repositioning |
| title | Anticancer Activity of Pyrimethamine via Ubiquitin Mediated Degradation of AIMP2-DX2 |
| title_full | Anticancer Activity of Pyrimethamine via Ubiquitin Mediated Degradation of AIMP2-DX2 |
| title_fullStr | Anticancer Activity of Pyrimethamine via Ubiquitin Mediated Degradation of AIMP2-DX2 |
| title_full_unstemmed | Anticancer Activity of Pyrimethamine via Ubiquitin Mediated Degradation of AIMP2-DX2 |
| title_short | Anticancer Activity of Pyrimethamine via Ubiquitin Mediated Degradation of AIMP2-DX2 |
| title_sort | anticancer activity of pyrimethamine via ubiquitin mediated degradation of aimp2 dx2 |
| topic | pyrimethamine AIMP2-DX2 ubiquitination anticancer drug repositioning |
| url | https://www.mdpi.com/1420-3049/25/12/2763 |
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