LCK facilitates DNA damage repair by stabilizing RAD51 and BRCA1 in the nucleus of chemoresistant ovarian cancer
Abstract Poly-ADP Ribose Polymerase (PARP) targeted therapy is clinically approved for the treatment of homologous recombination (HR) repair deficient tumors. The remarkable success of this therapy in the treatment of HR repair deficient cancers has not translated to HR-proficient cancers. Our studi...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-06-01
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| Series: | Journal of Ovarian Research |
| Online Access: | https://doi.org/10.1186/s13048-023-01194-2 |
| _version_ | 1797789618918129664 |
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| author | Goutam Dey Rashmi Bharti Chad Braley Ravi Alluri Emily Esakov Katie Crean-Tate Keith McCrae Amy Joehlin-Price Peter G. Rose Justin Lathia Zihua Gong Ofer Reizes |
| author_facet | Goutam Dey Rashmi Bharti Chad Braley Ravi Alluri Emily Esakov Katie Crean-Tate Keith McCrae Amy Joehlin-Price Peter G. Rose Justin Lathia Zihua Gong Ofer Reizes |
| author_sort | Goutam Dey |
| collection | DOAJ |
| description | Abstract Poly-ADP Ribose Polymerase (PARP) targeted therapy is clinically approved for the treatment of homologous recombination (HR) repair deficient tumors. The remarkable success of this therapy in the treatment of HR repair deficient cancers has not translated to HR-proficient cancers. Our studies identify the novel role of non-receptor lymphocyte-specific protein tyrosine kinase (LCK) in the regulation of HR repair in endometrioid epithelial ovarian cancer (eEOC) model. We show that DNA damage leads to direct interaction of LCK with the HR repair proteins RAD51 and BRCA1 in a kinase dependent manner RAD51 and BRCA1 stabilization. LCK expression is induced and activated in the nucleus in response to DNA damage insult. Disruption of LCK expression attenuates RAD51, BRCA1, and BRCA2 protein expression by hampering there stability and results in inhibition of HR-mediated DNA repair including suppression of RAD51 foci formation, and augmentation of γH2AX foci formation. In contrast LCK overexpression leads to increased RAD51 and BRCA1 expression with a concomitant increase in HR DNA damage repair. Importantly, attenuation of LCK sensitizes HR-proficient eEOC cells to PARP inhibitor in cells and pre-clinical mouse studies. Collectively, our findings identify a novel therapeutic strategy to expand the utility of PARP targeted therapy in HR proficient ovarian cancer. Graphical Abstract |
| first_indexed | 2024-03-13T01:53:14Z |
| format | Article |
| id | doaj.art-2717acaed3114fb5964d7b172163769d |
| institution | Directory Open Access Journal |
| issn | 1757-2215 |
| language | English |
| last_indexed | 2024-03-13T01:53:14Z |
| publishDate | 2023-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Ovarian Research |
| spelling | doaj.art-2717acaed3114fb5964d7b172163769d2023-07-02T11:23:04ZengBMCJournal of Ovarian Research1757-22152023-06-0116111910.1186/s13048-023-01194-2LCK facilitates DNA damage repair by stabilizing RAD51 and BRCA1 in the nucleus of chemoresistant ovarian cancerGoutam Dey0Rashmi Bharti1Chad Braley2Ravi Alluri3Emily Esakov4Katie Crean-Tate5Keith McCrae6Amy Joehlin-Price7Peter G. Rose8Justin Lathia9Zihua Gong10Ofer Reizes11Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic FoundationDepartment of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic FoundationDepartment of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic FoundationDepartment of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic FoundationDepartment of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic FoundationDivision of Gynecologic Cancer, Women’s Health Institute, Cleveland ClinicDepartment of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic FoundationPathology and Lab Medicine, Cleveland ClinicDivision of Gynecologic Cancer, Women’s Health Institute, Cleveland ClinicDepartment of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic FoundationCase Comprehensive Cancer CenterDepartment of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic FoundationAbstract Poly-ADP Ribose Polymerase (PARP) targeted therapy is clinically approved for the treatment of homologous recombination (HR) repair deficient tumors. The remarkable success of this therapy in the treatment of HR repair deficient cancers has not translated to HR-proficient cancers. Our studies identify the novel role of non-receptor lymphocyte-specific protein tyrosine kinase (LCK) in the regulation of HR repair in endometrioid epithelial ovarian cancer (eEOC) model. We show that DNA damage leads to direct interaction of LCK with the HR repair proteins RAD51 and BRCA1 in a kinase dependent manner RAD51 and BRCA1 stabilization. LCK expression is induced and activated in the nucleus in response to DNA damage insult. Disruption of LCK expression attenuates RAD51, BRCA1, and BRCA2 protein expression by hampering there stability and results in inhibition of HR-mediated DNA repair including suppression of RAD51 foci formation, and augmentation of γH2AX foci formation. In contrast LCK overexpression leads to increased RAD51 and BRCA1 expression with a concomitant increase in HR DNA damage repair. Importantly, attenuation of LCK sensitizes HR-proficient eEOC cells to PARP inhibitor in cells and pre-clinical mouse studies. Collectively, our findings identify a novel therapeutic strategy to expand the utility of PARP targeted therapy in HR proficient ovarian cancer. Graphical Abstracthttps://doi.org/10.1186/s13048-023-01194-2 |
| spellingShingle | Goutam Dey Rashmi Bharti Chad Braley Ravi Alluri Emily Esakov Katie Crean-Tate Keith McCrae Amy Joehlin-Price Peter G. Rose Justin Lathia Zihua Gong Ofer Reizes LCK facilitates DNA damage repair by stabilizing RAD51 and BRCA1 in the nucleus of chemoresistant ovarian cancer Journal of Ovarian Research |
| title | LCK facilitates DNA damage repair by stabilizing RAD51 and BRCA1 in the nucleus of chemoresistant ovarian cancer |
| title_full | LCK facilitates DNA damage repair by stabilizing RAD51 and BRCA1 in the nucleus of chemoresistant ovarian cancer |
| title_fullStr | LCK facilitates DNA damage repair by stabilizing RAD51 and BRCA1 in the nucleus of chemoresistant ovarian cancer |
| title_full_unstemmed | LCK facilitates DNA damage repair by stabilizing RAD51 and BRCA1 in the nucleus of chemoresistant ovarian cancer |
| title_short | LCK facilitates DNA damage repair by stabilizing RAD51 and BRCA1 in the nucleus of chemoresistant ovarian cancer |
| title_sort | lck facilitates dna damage repair by stabilizing rad51 and brca1 in the nucleus of chemoresistant ovarian cancer |
| url | https://doi.org/10.1186/s13048-023-01194-2 |
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