2-Hydroxy-3-methylanthraquinone inhibits homologous recombination repair in osteosarcoma through the MYC-CHK1-RAD51 axis
Abstract Background Osteosarcoma is a malignant bone tumor that usually affects adolescents aged 15–19 y. The DNA damage response (DDR) is significantly enhanced in osteosarcoma, impairing the effect of systemic chemotherapy. Targeting the DDR process was considered a feasible strategy benefitting o...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-01-01
|
| Series: | Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s10020-023-00611-y |
| _version_ | 1811171664942071808 |
|---|---|
| author | Doudou Jing Xuanzuo Chen Zhenhao Zhang Fengxia Chen Fuhua Huang Zhicai Zhang Wei Wu Zengwu Shao Feifei Pu |
| author_facet | Doudou Jing Xuanzuo Chen Zhenhao Zhang Fengxia Chen Fuhua Huang Zhicai Zhang Wei Wu Zengwu Shao Feifei Pu |
| author_sort | Doudou Jing |
| collection | DOAJ |
| description | Abstract Background Osteosarcoma is a malignant bone tumor that usually affects adolescents aged 15–19 y. The DNA damage response (DDR) is significantly enhanced in osteosarcoma, impairing the effect of systemic chemotherapy. Targeting the DDR process was considered a feasible strategy benefitting osteosarcoma patients. However, the clinical application of DDR inhibitors is not impressive because of their side effects. Chinese herbal medicines with high anti-tumor effects and low toxicity in the human body have gradually gained attention. 2-Hydroxy-3-methylanthraquinone (HMA), a Chinese medicine monomer found in the extract of Oldenlandia diffusa, exerts significant inhibitory effects on various tumors. However, its anti-osteosarcoma effects and defined molecular mechanisms have not been reported. Methods After HMA treatment, the proliferation and metastasis capacity of osteosarcoma cells was detected by CCK-8, colony formation, transwell assays and Annexin V-fluorescein isothiocyanate/propidium iodide staining. RNA-sequence, plasmid infection, RNA interference, Western blotting and immunofluorescence assay were used to investigate the molecular mechanism and effects of HMA inhibiting osteosarcoma. Rescue assay and CHIP assay was used to further verified the relationship between MYC, CHK1 and RAD51. Results HMA regulate MYC to inhibit osteosarcoma proliferation and DNA damage repair through PI3K/AKT signaling pathway. The results of RNA-seq, IHC, Western boltting etc. showed relationship between MYC, CHK1 and RAD51. Rescue assay and CHIP assay further verified HMA can impair homologous recombination repair through the MYC-CHK1-RAD51 pathway. Conclusion HMA significantly inhibits osteosarcoma proliferation and homologous recombination repair through the MYC-CHK1-RAD51 pathway, which is mediated by the PI3K-AKT signaling pathway. This study investigated the exact mechanism of the anti-osteosarcoma effect of HMA and provided a potential feasible strategy for the clinical treatment of human osteosarcoma. Graphical Abstract |
| first_indexed | 2024-04-10T17:18:48Z |
| format | Article |
| id | doaj.art-ddc202f177e14343b4c9349d1b4467fa |
| institution | Directory Open Access Journal |
| issn | 1528-3658 |
| language | English |
| last_indexed | 2024-04-10T17:18:48Z |
| publishDate | 2023-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Medicine |
| spelling | doaj.art-ddc202f177e14343b4c9349d1b4467fa2023-02-05T12:16:01ZengBMCMolecular Medicine1528-36582023-01-0129111410.1186/s10020-023-00611-y2-Hydroxy-3-methylanthraquinone inhibits homologous recombination repair in osteosarcoma through the MYC-CHK1-RAD51 axisDoudou Jing0Xuanzuo Chen1Zhenhao Zhang2Fengxia Chen3Fuhua Huang4Zhicai Zhang5Wei Wu6Zengwu Shao7Feifei Pu8Department of Orthopaedics, The Second Hospital of Shanxi Medical UniversityDepartment of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Radiation and Medical Oncology, Zhongnan Hospital, Wuhan UniversityDepartment of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyAbstract Background Osteosarcoma is a malignant bone tumor that usually affects adolescents aged 15–19 y. The DNA damage response (DDR) is significantly enhanced in osteosarcoma, impairing the effect of systemic chemotherapy. Targeting the DDR process was considered a feasible strategy benefitting osteosarcoma patients. However, the clinical application of DDR inhibitors is not impressive because of their side effects. Chinese herbal medicines with high anti-tumor effects and low toxicity in the human body have gradually gained attention. 2-Hydroxy-3-methylanthraquinone (HMA), a Chinese medicine monomer found in the extract of Oldenlandia diffusa, exerts significant inhibitory effects on various tumors. However, its anti-osteosarcoma effects and defined molecular mechanisms have not been reported. Methods After HMA treatment, the proliferation and metastasis capacity of osteosarcoma cells was detected by CCK-8, colony formation, transwell assays and Annexin V-fluorescein isothiocyanate/propidium iodide staining. RNA-sequence, plasmid infection, RNA interference, Western blotting and immunofluorescence assay were used to investigate the molecular mechanism and effects of HMA inhibiting osteosarcoma. Rescue assay and CHIP assay was used to further verified the relationship between MYC, CHK1 and RAD51. Results HMA regulate MYC to inhibit osteosarcoma proliferation and DNA damage repair through PI3K/AKT signaling pathway. The results of RNA-seq, IHC, Western boltting etc. showed relationship between MYC, CHK1 and RAD51. Rescue assay and CHIP assay further verified HMA can impair homologous recombination repair through the MYC-CHK1-RAD51 pathway. Conclusion HMA significantly inhibits osteosarcoma proliferation and homologous recombination repair through the MYC-CHK1-RAD51 pathway, which is mediated by the PI3K-AKT signaling pathway. This study investigated the exact mechanism of the anti-osteosarcoma effect of HMA and provided a potential feasible strategy for the clinical treatment of human osteosarcoma. Graphical Abstracthttps://doi.org/10.1186/s10020-023-00611-y2-Hydroxy-3-methylanthraquinoneDNA damage response (DDR)MYCCHK1RAD51 |
| spellingShingle | Doudou Jing Xuanzuo Chen Zhenhao Zhang Fengxia Chen Fuhua Huang Zhicai Zhang Wei Wu Zengwu Shao Feifei Pu 2-Hydroxy-3-methylanthraquinone inhibits homologous recombination repair in osteosarcoma through the MYC-CHK1-RAD51 axis Molecular Medicine 2-Hydroxy-3-methylanthraquinone DNA damage response (DDR) MYC CHK1 RAD51 |
| title | 2-Hydroxy-3-methylanthraquinone inhibits homologous recombination repair in osteosarcoma through the MYC-CHK1-RAD51 axis |
| title_full | 2-Hydroxy-3-methylanthraquinone inhibits homologous recombination repair in osteosarcoma through the MYC-CHK1-RAD51 axis |
| title_fullStr | 2-Hydroxy-3-methylanthraquinone inhibits homologous recombination repair in osteosarcoma through the MYC-CHK1-RAD51 axis |
| title_full_unstemmed | 2-Hydroxy-3-methylanthraquinone inhibits homologous recombination repair in osteosarcoma through the MYC-CHK1-RAD51 axis |
| title_short | 2-Hydroxy-3-methylanthraquinone inhibits homologous recombination repair in osteosarcoma through the MYC-CHK1-RAD51 axis |
| title_sort | 2 hydroxy 3 methylanthraquinone inhibits homologous recombination repair in osteosarcoma through the myc chk1 rad51 axis |
| topic | 2-Hydroxy-3-methylanthraquinone DNA damage response (DDR) MYC CHK1 RAD51 |
| url | https://doi.org/10.1186/s10020-023-00611-y |
| work_keys_str_mv | AT doudoujing 2hydroxy3methylanthraquinoneinhibitshomologousrecombinationrepairinosteosarcomathroughthemycchk1rad51axis AT xuanzuochen 2hydroxy3methylanthraquinoneinhibitshomologousrecombinationrepairinosteosarcomathroughthemycchk1rad51axis AT zhenhaozhang 2hydroxy3methylanthraquinoneinhibitshomologousrecombinationrepairinosteosarcomathroughthemycchk1rad51axis AT fengxiachen 2hydroxy3methylanthraquinoneinhibitshomologousrecombinationrepairinosteosarcomathroughthemycchk1rad51axis AT fuhuahuang 2hydroxy3methylanthraquinoneinhibitshomologousrecombinationrepairinosteosarcomathroughthemycchk1rad51axis AT zhicaizhang 2hydroxy3methylanthraquinoneinhibitshomologousrecombinationrepairinosteosarcomathroughthemycchk1rad51axis AT weiwu 2hydroxy3methylanthraquinoneinhibitshomologousrecombinationrepairinosteosarcomathroughthemycchk1rad51axis AT zengwushao 2hydroxy3methylanthraquinoneinhibitshomologousrecombinationrepairinosteosarcomathroughthemycchk1rad51axis AT feifeipu 2hydroxy3methylanthraquinoneinhibitshomologousrecombinationrepairinosteosarcomathroughthemycchk1rad51axis |