PARP inhibitors elicit a cellular senescence mediated inflammatory response in homologous recombination proficient cancer cells
Abstract Poly (ADP-ribose) polymerase (PARP) inhibitors have improved the prognosis of homologous recombination deficient (HRD) ovarian cancer (OC), while effective therapeutic strategies for HR-proficient (HRP) OC still need to be established. This study investigates senescence-mediated inflammatio...
Saved in:
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-05-01
|
| Series: | Scientific Reports |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/s41598-025-00336-4 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850284390905544704 |
|---|---|
| author | Misato Kamii Ryo Kamata Hitoshi Saito Gaku Yamamoto Chiaki Mashima Toyohiro Yamauchi Takehiro Nakao Yuta Sakae Tomoko Yamamori-Morita Kazuki Nakai Yumi Hakozaki Masataka Takenaka Aikou Okamoto Akihiro Ohashi |
| author_facet | Misato Kamii Ryo Kamata Hitoshi Saito Gaku Yamamoto Chiaki Mashima Toyohiro Yamauchi Takehiro Nakao Yuta Sakae Tomoko Yamamori-Morita Kazuki Nakai Yumi Hakozaki Masataka Takenaka Aikou Okamoto Akihiro Ohashi |
| author_sort | Misato Kamii |
| collection | DOAJ |
| description | Abstract Poly (ADP-ribose) polymerase (PARP) inhibitors have improved the prognosis of homologous recombination deficient (HRD) ovarian cancer (OC), while effective therapeutic strategies for HR-proficient (HRP) OC still need to be established. This study investigates senescence-mediated inflammation as a novel mechanism of action for PARP inhibitors in HRP cancers. Transcriptome analyses were performed in olaparib-treated HeLa cells as a HRP model. Interferon regulatory factor-Lucia luciferase (IRF-Luc) reporter activity was assessed. The effects of PARP inhibitors on senescence-like phenotypes were assessed in seven HRP cancer cell lines, based on morphological changes, senescence-associated β-galactosidase (SA-β-GAL) activity, cellular granularity, and senescence-associated secretory phenotype (SASP)-related gene expression. Peripheral blood mononuclear cell (PBMC) migration assays were also performed with the conditioned medium in treatment with the PARP inhibitor. Transcriptome analyses revealed numbers of inflammatory cytokine- and chemokine-related pathways were significantly upregulated in olaparib-treated HeLa cells, which were confirmed by IRF-Luc reporter assays. The PARP inhibitors induced senescent phenotypes in HRP cancer cell lines: flattened and enlarged morphology, increased SA-β-GAL activity, elevated cellular granularity, and upregulated expressions of SASP-related genes (e.g., IL1B, IL6, and CXCL10). Furthermore, in vitro migration assays revealed that PARP inhibitor-treated HRP cancer cells attracted PBMCs more abundantly, suggesting the potential for recruiting immune cells to HRP cancer cells through senescence-mediated immunological activation. Our findings suggest that PARP inhibitors recruit immune cells to HRP cancer cells, potentially activating immune responses in the tumor microenvironment, providing new insights into the clinical benefits of PARP inhibitors in immunotherapy for patients with HRP OC. |
| format | Article |
| id | doaj-art-8b95a5903e174685a3c9b8e2dffe82c9 |
| institution | OA Journals |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-8b95a5903e174685a3c9b8e2dffe82c92025-08-20T01:47:34ZengNature PortfolioScientific Reports2045-23222025-05-0115111210.1038/s41598-025-00336-4PARP inhibitors elicit a cellular senescence mediated inflammatory response in homologous recombination proficient cancer cellsMisato Kamii0Ryo Kamata1Hitoshi Saito2Gaku Yamamoto3Chiaki Mashima4Toyohiro Yamauchi5Takehiro Nakao6Yuta Sakae7Tomoko Yamamori-Morita8Kazuki Nakai9Yumi Hakozaki10Masataka Takenaka11Aikou Okamoto12Akihiro Ohashi13Division of Collaborative Research and Developments, Exploratory Oncology Research & Clinical Trial Center, National Cancer CenterDivision of Collaborative Research and Developments, Exploratory Oncology Research & Clinical Trial Center, National Cancer CenterDivision of Collaborative Research and Developments, Exploratory Oncology Research & Clinical Trial Center, National Cancer CenterDivision of Collaborative Research and Developments, Exploratory Oncology Research & Clinical Trial Center, National Cancer CenterDivision of Collaborative Research and Developments, Exploratory Oncology Research & Clinical Trial Center, National Cancer CenterDivision of Collaborative Research and Developments, Exploratory Oncology Research & Clinical Trial Center, National Cancer CenterDivision of Collaborative Research and Developments, Exploratory Oncology Research & Clinical Trial Center, National Cancer CenterDivision of Collaborative Research and Developments, Exploratory Oncology Research & Clinical Trial Center, National Cancer CenterDivision of Collaborative Research and Developments, Exploratory Oncology Research & Clinical Trial Center, National Cancer CenterDivision of Collaborative Research and Developments, Exploratory Oncology Research & Clinical Trial Center, National Cancer CenterDivision of Collaborative Research and Developments, Exploratory Oncology Research & Clinical Trial Center, National Cancer CenterDepartment of Obstetrics and Gynecology, The Jikei University School of MedicineDepartment of Obstetrics and Gynecology, The Jikei University School of MedicineDivision of Collaborative Research and Developments, Exploratory Oncology Research & Clinical Trial Center, National Cancer CenterAbstract Poly (ADP-ribose) polymerase (PARP) inhibitors have improved the prognosis of homologous recombination deficient (HRD) ovarian cancer (OC), while effective therapeutic strategies for HR-proficient (HRP) OC still need to be established. This study investigates senescence-mediated inflammation as a novel mechanism of action for PARP inhibitors in HRP cancers. Transcriptome analyses were performed in olaparib-treated HeLa cells as a HRP model. Interferon regulatory factor-Lucia luciferase (IRF-Luc) reporter activity was assessed. The effects of PARP inhibitors on senescence-like phenotypes were assessed in seven HRP cancer cell lines, based on morphological changes, senescence-associated β-galactosidase (SA-β-GAL) activity, cellular granularity, and senescence-associated secretory phenotype (SASP)-related gene expression. Peripheral blood mononuclear cell (PBMC) migration assays were also performed with the conditioned medium in treatment with the PARP inhibitor. Transcriptome analyses revealed numbers of inflammatory cytokine- and chemokine-related pathways were significantly upregulated in olaparib-treated HeLa cells, which were confirmed by IRF-Luc reporter assays. The PARP inhibitors induced senescent phenotypes in HRP cancer cell lines: flattened and enlarged morphology, increased SA-β-GAL activity, elevated cellular granularity, and upregulated expressions of SASP-related genes (e.g., IL1B, IL6, and CXCL10). Furthermore, in vitro migration assays revealed that PARP inhibitor-treated HRP cancer cells attracted PBMCs more abundantly, suggesting the potential for recruiting immune cells to HRP cancer cells through senescence-mediated immunological activation. Our findings suggest that PARP inhibitors recruit immune cells to HRP cancer cells, potentially activating immune responses in the tumor microenvironment, providing new insights into the clinical benefits of PARP inhibitors in immunotherapy for patients with HRP OC.https://doi.org/10.1038/s41598-025-00336-4Poly (ADP-ribose) polymerase (PARP) inhibitorsHomologous recombination-proficient (HRP) cancerOvarian cancer (OC)Senescence-associated secretory phenotype (SASP) |
| spellingShingle | Misato Kamii Ryo Kamata Hitoshi Saito Gaku Yamamoto Chiaki Mashima Toyohiro Yamauchi Takehiro Nakao Yuta Sakae Tomoko Yamamori-Morita Kazuki Nakai Yumi Hakozaki Masataka Takenaka Aikou Okamoto Akihiro Ohashi PARP inhibitors elicit a cellular senescence mediated inflammatory response in homologous recombination proficient cancer cells Scientific Reports Poly (ADP-ribose) polymerase (PARP) inhibitors Homologous recombination-proficient (HRP) cancer Ovarian cancer (OC) Senescence-associated secretory phenotype (SASP) |
| title | PARP inhibitors elicit a cellular senescence mediated inflammatory response in homologous recombination proficient cancer cells |
| title_full | PARP inhibitors elicit a cellular senescence mediated inflammatory response in homologous recombination proficient cancer cells |
| title_fullStr | PARP inhibitors elicit a cellular senescence mediated inflammatory response in homologous recombination proficient cancer cells |
| title_full_unstemmed | PARP inhibitors elicit a cellular senescence mediated inflammatory response in homologous recombination proficient cancer cells |
| title_short | PARP inhibitors elicit a cellular senescence mediated inflammatory response in homologous recombination proficient cancer cells |
| title_sort | parp inhibitors elicit a cellular senescence mediated inflammatory response in homologous recombination proficient cancer cells |
| topic | Poly (ADP-ribose) polymerase (PARP) inhibitors Homologous recombination-proficient (HRP) cancer Ovarian cancer (OC) Senescence-associated secretory phenotype (SASP) |
| url | https://doi.org/10.1038/s41598-025-00336-4 |
| work_keys_str_mv | AT misatokamii parpinhibitorselicitacellularsenescencemediatedinflammatoryresponseinhomologousrecombinationproficientcancercells AT ryokamata parpinhibitorselicitacellularsenescencemediatedinflammatoryresponseinhomologousrecombinationproficientcancercells AT hitoshisaito parpinhibitorselicitacellularsenescencemediatedinflammatoryresponseinhomologousrecombinationproficientcancercells AT gakuyamamoto parpinhibitorselicitacellularsenescencemediatedinflammatoryresponseinhomologousrecombinationproficientcancercells AT chiakimashima parpinhibitorselicitacellularsenescencemediatedinflammatoryresponseinhomologousrecombinationproficientcancercells AT toyohiroyamauchi parpinhibitorselicitacellularsenescencemediatedinflammatoryresponseinhomologousrecombinationproficientcancercells AT takehironakao parpinhibitorselicitacellularsenescencemediatedinflammatoryresponseinhomologousrecombinationproficientcancercells AT yutasakae parpinhibitorselicitacellularsenescencemediatedinflammatoryresponseinhomologousrecombinationproficientcancercells AT tomokoyamamorimorita parpinhibitorselicitacellularsenescencemediatedinflammatoryresponseinhomologousrecombinationproficientcancercells AT kazukinakai parpinhibitorselicitacellularsenescencemediatedinflammatoryresponseinhomologousrecombinationproficientcancercells AT yumihakozaki parpinhibitorselicitacellularsenescencemediatedinflammatoryresponseinhomologousrecombinationproficientcancercells AT masatakatakenaka parpinhibitorselicitacellularsenescencemediatedinflammatoryresponseinhomologousrecombinationproficientcancercells AT aikouokamoto parpinhibitorselicitacellularsenescencemediatedinflammatoryresponseinhomologousrecombinationproficientcancercells AT akihiroohashi parpinhibitorselicitacellularsenescencemediatedinflammatoryresponseinhomologousrecombinationproficientcancercells |