Targeting PARG induces tumor cell growth inhibition and antitumor immune response by reducing phosphorylated STAT3 in ovarian cancer
Background Ovarian cancer is the most lethal gynecological malignancy, with limited treatment options after failure of standard therapies. Despite the potential of poly(ADP-ribose) polymerase inhibitors in treating DNA damage response (DDR)-deficient ovarian cancer, the development of resistance and...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2024-04-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/12/4/e007716.full |
| _version_ | 1826980383457017856 |
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| author | Lorna Rodriguez-Rodriguez Rui Huang Mihaela Cristea Qianqian Zhao Adrian Kohut Hua Yu Mihae Song Antons Martincuks Chunyan Zhang Edward W Wang Theresa Austria Yi-Jia Li Nicole Lugo Santiago Rosemarie Martinez Borrero Binghui Shen |
| author_facet | Lorna Rodriguez-Rodriguez Rui Huang Mihaela Cristea Qianqian Zhao Adrian Kohut Hua Yu Mihae Song Antons Martincuks Chunyan Zhang Edward W Wang Theresa Austria Yi-Jia Li Nicole Lugo Santiago Rosemarie Martinez Borrero Binghui Shen |
| author_sort | Lorna Rodriguez-Rodriguez |
| collection | DOAJ |
| description | Background Ovarian cancer is the most lethal gynecological malignancy, with limited treatment options after failure of standard therapies. Despite the potential of poly(ADP-ribose) polymerase inhibitors in treating DNA damage response (DDR)-deficient ovarian cancer, the development of resistance and immunosuppression limit their efficacy, necessitating alternative therapeutic strategies. Inhibitors of poly(ADP-ribose) glycohydrolase (PARG) represent a novel class of inhibitors that are currently being assessed in preclinical and clinical studies for cancer treatment.Methods By using a PARG small-molecule inhibitor, COH34, and a cell-penetrating antibody targeting the PARG’s catalytic domain, we investigated the effects of PARG inhibition on signal transducer and activator of transcription 3 (STAT3) in OVCAR8, PEO1, and Brca1-null ID8 ovarian cancer cell lines, as well as in immune cells. We examined PARG inhibition-induced effects on STAT3 phosphorylation, nuclear localization, target gene expression, and antitumor immune responses in vitro, in patient-derived tumor organoids, and in an immunocompetent Brca1-null ID8 ovarian mouse tumor model that mirrors DDR-deficient human high-grade serous ovarian cancer. We also tested the effects of overexpressing a constitutively activated STAT3 mutant on COH34-induced tumor cell growth inhibition.Results Our findings show that PARG inhibition downregulates STAT3 activity through dephosphorylation in ovarian cancer cells. Importantly, overexpression of a constitutively activated STAT3 mutant in tumor cells attenuates PARG inhibitor-induced growth inhibition. Additionally, PARG inhibition reduces STAT3 phosphorylation in immune cells, leading to the activation of antitumor immune responses, shown in immune cells cocultured with ovarian cancer patient tumor-derived organoids and in immune-competent mice-bearing mouse ovarian tumors.Conclusions We have identified a novel antitumor mechanism underlying PARG inhibition beyond its primary antitumor effects through blocking DDR in ovarian cancer. Furthermore, targeting PARG activates antitumor immune responses, thereby potentially increasing response rates to immunotherapy in patients with ovarian cancer. |
| first_indexed | 2024-04-24T12:52:57Z |
| format | Article |
| id | doaj.art-29ce33204b0e45249cb86e478b123daa |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2025-02-18T05:45:28Z |
| publishDate | 2024-04-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-29ce33204b0e45249cb86e478b123daa2024-11-14T03:30:10ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262024-04-0112410.1136/jitc-2023-007716Targeting PARG induces tumor cell growth inhibition and antitumor immune response by reducing phosphorylated STAT3 in ovarian cancerLorna Rodriguez-Rodriguez0Rui Huang1Mihaela Cristea2Qianqian Zhao3Adrian Kohut4Hua Yu5Mihae Song6Antons Martincuks7Chunyan Zhang8Edward W Wang9Theresa Austria10Yi-Jia Li11Nicole Lugo Santiago12Rosemarie Martinez Borrero13Binghui Shen14Department of Surgery, City of Hope National Medical Center, Duarte, California, USADepartment of Immuno-Oncology, City of Hope Comprehensive Cancer Center, Duarte, California, USADepartment of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, California, USADepartment of Immuno-Oncology, City of Hope Comprehensive Cancer Center, Duarte, California, USADepartment of Surgery, City of Hope National Medical Center, Duarte, California, USADepartment of Immuno-Oncology, City of Hope Comprehensive Cancer Center, Duarte, California, USADepartment of Surgery, City of Hope National Medical Center, Duarte, California, USADepartment of Immuno-Oncology, City of Hope Comprehensive Cancer Center, Duarte, California, USADepartment of Immuno-Oncology, City of Hope Comprehensive Cancer Center, Duarte, California, USADepartment of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, California, USADepartment of Immuno-Oncology, City of Hope Comprehensive Cancer Center, Duarte, California, USADepartment of Immuno-Oncology, City of Hope Comprehensive Cancer Center, Duarte, California, USADivision of Gynecologic Oncology, Department of Surgery, City of Hope Comprehensive Cancer Center, Duarte, California, USADepartment of Immuno-Oncology, City of Hope Comprehensive Cancer Center, Duarte, California, USADepartment of Cancer Genetics and Epigenetics, City of Hope Comprehensive Cancer Center, Duarte, California, USABackground Ovarian cancer is the most lethal gynecological malignancy, with limited treatment options after failure of standard therapies. Despite the potential of poly(ADP-ribose) polymerase inhibitors in treating DNA damage response (DDR)-deficient ovarian cancer, the development of resistance and immunosuppression limit their efficacy, necessitating alternative therapeutic strategies. Inhibitors of poly(ADP-ribose) glycohydrolase (PARG) represent a novel class of inhibitors that are currently being assessed in preclinical and clinical studies for cancer treatment.Methods By using a PARG small-molecule inhibitor, COH34, and a cell-penetrating antibody targeting the PARG’s catalytic domain, we investigated the effects of PARG inhibition on signal transducer and activator of transcription 3 (STAT3) in OVCAR8, PEO1, and Brca1-null ID8 ovarian cancer cell lines, as well as in immune cells. We examined PARG inhibition-induced effects on STAT3 phosphorylation, nuclear localization, target gene expression, and antitumor immune responses in vitro, in patient-derived tumor organoids, and in an immunocompetent Brca1-null ID8 ovarian mouse tumor model that mirrors DDR-deficient human high-grade serous ovarian cancer. We also tested the effects of overexpressing a constitutively activated STAT3 mutant on COH34-induced tumor cell growth inhibition.Results Our findings show that PARG inhibition downregulates STAT3 activity through dephosphorylation in ovarian cancer cells. Importantly, overexpression of a constitutively activated STAT3 mutant in tumor cells attenuates PARG inhibitor-induced growth inhibition. Additionally, PARG inhibition reduces STAT3 phosphorylation in immune cells, leading to the activation of antitumor immune responses, shown in immune cells cocultured with ovarian cancer patient tumor-derived organoids and in immune-competent mice-bearing mouse ovarian tumors.Conclusions We have identified a novel antitumor mechanism underlying PARG inhibition beyond its primary antitumor effects through blocking DDR in ovarian cancer. Furthermore, targeting PARG activates antitumor immune responses, thereby potentially increasing response rates to immunotherapy in patients with ovarian cancer.https://jitc.bmj.com/content/12/4/e007716.full |
| spellingShingle | Lorna Rodriguez-Rodriguez Rui Huang Mihaela Cristea Qianqian Zhao Adrian Kohut Hua Yu Mihae Song Antons Martincuks Chunyan Zhang Edward W Wang Theresa Austria Yi-Jia Li Nicole Lugo Santiago Rosemarie Martinez Borrero Binghui Shen Targeting PARG induces tumor cell growth inhibition and antitumor immune response by reducing phosphorylated STAT3 in ovarian cancer Journal for ImmunoTherapy of Cancer |
| title | Targeting PARG induces tumor cell growth inhibition and antitumor immune response by reducing phosphorylated STAT3 in ovarian cancer |
| title_full | Targeting PARG induces tumor cell growth inhibition and antitumor immune response by reducing phosphorylated STAT3 in ovarian cancer |
| title_fullStr | Targeting PARG induces tumor cell growth inhibition and antitumor immune response by reducing phosphorylated STAT3 in ovarian cancer |
| title_full_unstemmed | Targeting PARG induces tumor cell growth inhibition and antitumor immune response by reducing phosphorylated STAT3 in ovarian cancer |
| title_short | Targeting PARG induces tumor cell growth inhibition and antitumor immune response by reducing phosphorylated STAT3 in ovarian cancer |
| title_sort | targeting parg induces tumor cell growth inhibition and antitumor immune response by reducing phosphorylated stat3 in ovarian cancer |
| url | https://jitc.bmj.com/content/12/4/e007716.full |
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