PARP inhibitor exerts an anti-tumor effect via LMO2 and synergizes with cisplatin in natural killer/T cell lymphoma
Abstract Background PARP inhibitor (PARPi), as a kind of DNA damage repair inhibitor, has been shown to be effective in various solid tumors and hematologic malignancies. Natural killer/T cell lymphoma (NKTCL) is a highly aggressive malignancy, the treatment of which has long been a major challenge...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-07-01
|
| Series: | BMC Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12916-023-02904-9 |
| _version_ | 1827899848142094336 |
|---|---|
| author | Jiazhuo Wu Cunzhen Shi Hongwen Li Wenting Song Shuo Huang Jianxiang Zhang Wencai Li Zhaoming Li Mingzhi Zhang |
| author_facet | Jiazhuo Wu Cunzhen Shi Hongwen Li Wenting Song Shuo Huang Jianxiang Zhang Wencai Li Zhaoming Li Mingzhi Zhang |
| author_sort | Jiazhuo Wu |
| collection | DOAJ |
| description | Abstract Background PARP inhibitor (PARPi), as a kind of DNA damage repair inhibitor, has been shown to be effective in various solid tumors and hematologic malignancies. Natural killer/T cell lymphoma (NKTCL) is a highly aggressive malignancy, the treatment of which has long been a major challenge in the clinic. Here, we investigated the efficacy and mechanism of PARPi, and the therapeutic value of PARPi combined with cisplatin in NKTCL. Methods The cell proliferation, cell apoptosis, and cell cycle of NKTCL cells were detected respectively by CCK-8 and flow cytometry. The changes of mRNA expression and protein level were measured respectively by mRNA-sequencing, quantitative real-time PCR, western blotting, and immunofluorescence. LMO2 expression was detected by immunohistochemistry and western blotting. Targeted knockdown of LMO2 was conducted by short hairpin RNA. The tumor xenograft models were established to evaluate the efficacy of drugs in vivo. Results PARPi inhibited cell proliferation, promoted cell apoptosis, and induced S-phase cell cycle arrest in NKTCL cells. PARPi led to the accumulation of DNA damage by blocking DNA repair and DNA replication. Additionally, LMO2 deficiency reduced the sensitivity of NKTCL cells to PARPi. Finally, the combination of PARPi and cisplatin exhibited significant synergistic effects both in vitro and in vivo. Conclusions In summary, we found that PARPi exerted an anti-tumor effect via LMO2 and synergized with cisplatin in NKTCL, which provides the theoretical basis for the clinical application of PARPi. |
| first_indexed | 2024-03-12T23:23:12Z |
| format | Article |
| id | doaj.art-577875a5eb8e4866863af0ebee8fbdee |
| institution | Directory Open Access Journal |
| issn | 1741-7015 |
| language | English |
| last_indexed | 2024-03-12T23:23:12Z |
| publishDate | 2023-07-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Medicine |
| spelling | doaj.art-577875a5eb8e4866863af0ebee8fbdee2023-07-16T11:19:14ZengBMCBMC Medicine1741-70152023-07-0121111110.1186/s12916-023-02904-9PARP inhibitor exerts an anti-tumor effect via LMO2 and synergizes with cisplatin in natural killer/T cell lymphomaJiazhuo Wu0Cunzhen Shi1Hongwen Li2Wenting Song3Shuo Huang4Jianxiang Zhang5Wencai Li6Zhaoming Li7Mingzhi Zhang8Department of Oncology, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Oncology, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Oncology, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Oncology, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Infectious Diseases and Hepatology, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Oncology, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Pathology, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Oncology, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Oncology, The First Affiliated Hospital of Zhengzhou UniversityAbstract Background PARP inhibitor (PARPi), as a kind of DNA damage repair inhibitor, has been shown to be effective in various solid tumors and hematologic malignancies. Natural killer/T cell lymphoma (NKTCL) is a highly aggressive malignancy, the treatment of which has long been a major challenge in the clinic. Here, we investigated the efficacy and mechanism of PARPi, and the therapeutic value of PARPi combined with cisplatin in NKTCL. Methods The cell proliferation, cell apoptosis, and cell cycle of NKTCL cells were detected respectively by CCK-8 and flow cytometry. The changes of mRNA expression and protein level were measured respectively by mRNA-sequencing, quantitative real-time PCR, western blotting, and immunofluorescence. LMO2 expression was detected by immunohistochemistry and western blotting. Targeted knockdown of LMO2 was conducted by short hairpin RNA. The tumor xenograft models were established to evaluate the efficacy of drugs in vivo. Results PARPi inhibited cell proliferation, promoted cell apoptosis, and induced S-phase cell cycle arrest in NKTCL cells. PARPi led to the accumulation of DNA damage by blocking DNA repair and DNA replication. Additionally, LMO2 deficiency reduced the sensitivity of NKTCL cells to PARPi. Finally, the combination of PARPi and cisplatin exhibited significant synergistic effects both in vitro and in vivo. Conclusions In summary, we found that PARPi exerted an anti-tumor effect via LMO2 and synergized with cisplatin in NKTCL, which provides the theoretical basis for the clinical application of PARPi.https://doi.org/10.1186/s12916-023-02904-9PARP inhibitorLMO2Natural killer/T cell lymphomaDNA damage repair |
| spellingShingle | Jiazhuo Wu Cunzhen Shi Hongwen Li Wenting Song Shuo Huang Jianxiang Zhang Wencai Li Zhaoming Li Mingzhi Zhang PARP inhibitor exerts an anti-tumor effect via LMO2 and synergizes with cisplatin in natural killer/T cell lymphoma BMC Medicine PARP inhibitor LMO2 Natural killer/T cell lymphoma DNA damage repair |
| title | PARP inhibitor exerts an anti-tumor effect via LMO2 and synergizes with cisplatin in natural killer/T cell lymphoma |
| title_full | PARP inhibitor exerts an anti-tumor effect via LMO2 and synergizes with cisplatin in natural killer/T cell lymphoma |
| title_fullStr | PARP inhibitor exerts an anti-tumor effect via LMO2 and synergizes with cisplatin in natural killer/T cell lymphoma |
| title_full_unstemmed | PARP inhibitor exerts an anti-tumor effect via LMO2 and synergizes with cisplatin in natural killer/T cell lymphoma |
| title_short | PARP inhibitor exerts an anti-tumor effect via LMO2 and synergizes with cisplatin in natural killer/T cell lymphoma |
| title_sort | parp inhibitor exerts an anti tumor effect via lmo2 and synergizes with cisplatin in natural killer t cell lymphoma |
| topic | PARP inhibitor LMO2 Natural killer/T cell lymphoma DNA damage repair |
| url | https://doi.org/10.1186/s12916-023-02904-9 |
| work_keys_str_mv | AT jiazhuowu parpinhibitorexertsanantitumoreffectvialmo2andsynergizeswithcisplatininnaturalkillertcelllymphoma AT cunzhenshi parpinhibitorexertsanantitumoreffectvialmo2andsynergizeswithcisplatininnaturalkillertcelllymphoma AT hongwenli parpinhibitorexertsanantitumoreffectvialmo2andsynergizeswithcisplatininnaturalkillertcelllymphoma AT wentingsong parpinhibitorexertsanantitumoreffectvialmo2andsynergizeswithcisplatininnaturalkillertcelllymphoma AT shuohuang parpinhibitorexertsanantitumoreffectvialmo2andsynergizeswithcisplatininnaturalkillertcelllymphoma AT jianxiangzhang parpinhibitorexertsanantitumoreffectvialmo2andsynergizeswithcisplatininnaturalkillertcelllymphoma AT wencaili parpinhibitorexertsanantitumoreffectvialmo2andsynergizeswithcisplatininnaturalkillertcelllymphoma AT zhaomingli parpinhibitorexertsanantitumoreffectvialmo2andsynergizeswithcisplatininnaturalkillertcelllymphoma AT mingzhizhang parpinhibitorexertsanantitumoreffectvialmo2andsynergizeswithcisplatininnaturalkillertcelllymphoma |