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The study tests paraspeckle component 1 (PSPC1) inhibition as an additional BRCA1/2 synthetic-lethal partner to potentiate olaparib. In vitro, olaparib plus PSPC1 siRNA yields synergistic growth inhibition, and in vivo it produces synergistic tumor suppression in xenograft mice. 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Enhancing sensitivity and preventing resistance is identified as an unmet clinical need.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How was PSPC1 tested as a partner to olaparib?",{"text":117,"@type":113},"The authors evaluated PSPC1 inhibition using PSPC1 small interfering RNA combined with olaparib in BRCA1/2-mutated breast and ovarian cancer cell models, and they assessed effects in a xenograft mouse model.",{"name":119,"@type":110,"acceptedAnswer":120},"What mechanistic effects support the synergy between olaparib and PSPC1 inhibition?",{"text":121,"@type":113},"Olaparib monotherapy increased p-ATM and DNA-PKcs expression, consistent with DNA repair activation, whereas combining PSPC1 siRNA with olaparib reduced these signals, increased H2AX foci, weakened G2/M checkpoint activation, and increased apoptosis.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},381931,1790319943,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":19,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},5909892330395,"https://ap-avatar.wpscdn.com/davatar_6f874abed73319feea01a86fa6f0fab8","Article  \nPSPC1 Inhibition Synergizes with Poly(ADP-ribose) Polymerase Inhibitors in a Preclinical Model of BRCA-Mutated Breast/Ovarian Cancer  \nMithun Ghosh 1, Min Sil Kang 1, Nar Bahadur Katuwal 1, Sa Deok Hong 1, Yeong Gyu Jeong 1, Seong Min Park 1, Seul-Gi Kim 2 and Yong Wha Moon 2, *  \nCitation: Ghosh, M.; Kang, M.S.; Katuwal, N.B.; Hong, S.D.; Jeong, Y.G.; Park, S.M.; Kim, S.-G.; Moon, Y.W. PSPC1 Inhibition Synergizes with Poly(ADP-ribose) Polymerase Inhibitors in a Preclinical Model of BRCA-Mutated Breast/Ovarian Cancer. Int. J. Mol. Sci. 2023, 24, 17086. [https://doi.org/](https://doi.org/)[ ](https://doi.org/)[10.3390/ijms242317086](10.3390/ijms242317086)  \nAcademic Editors: Masa-Aki Shibata and Sasagu Kurozumi  \nReceived: 16 November 2023  \nRevised: 30 November 2023  \nAccepted: 1 December 2023  \nPublished: 3 December 2023  \nCopyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \n1 Department of Biomedical Science, The Graduate School, CHA University, Seongnam-si 13488, Republic of Korea  \n2 Hematology and Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam-si 13496, Republic of Korea  \n* [Correspondence: ymoon@cha.ac.kr](Correspondence: ymoon@cha.ac.kr); Tel.: +82-31-780-3436; Fax: +82-31-780-3929  \nAbstract: Poly (ADP-ribose) polymerase (PARP) inhibitors are effective against BRCA1/2-mutated cancers through synthetic lethality. Unfortunately, most cases ultimately develop acquired resistance. Therefore, enhancing PARP inhibitor sensitivity and preventing resistance in those cells are an unmet clinical need. Here, we investigated the ability of paraspeckle component 1 (PSPC1), as an additional synthetic lethal partner with BRCA1/2, to enhance olaparib sensitivity in preclinical models of BRCA1/2-mutated breast and ovarian cancers. In vitro, the combined olaparib and PSPC1 small interfering RNA (siRNA) exhibited synergistic anti-proliferative activity in BRCA1/2-mutated breast and ovarian cancer cells. The combination therapy also demonstrated synergistic tumor inhibition in a xenograft mouse model. Mechanistically, olaparib monotherapy increased the expressions of p-ATM and DNA-PKcs, suggesting the activation of a DNA repair pathway, whereas combining PSPC1 siRNA with olaparib decreased the expressions of p-ATM and DNA-PKcs again. As such, the combination increased the formation of 􀀍H2AX foci, indicating stronger DNA double-strand breaks. Subsequently, these DNA-damaged cells escaped G2/M checkpoint activation, as indicated by the suppression of p-cdc25C (Ser216) and p-cdc2 (Tyr15) after combination treatment. Finally, these cells entered mitosis, which induced increased apoptosis. Thus, this proves that PSPC1 inhibition enhances olaparib sensitivity by targeting DNA damage response in our preclinical model. The combination of olaparib and PSPC1 inhibition merits further clinical investigation to enhance PARP inhibitor efficacy.  \nKeywords: PARP inhibitor; PSPC1; DNA double-strand break; sensitivity  \n1. Introduction  \nBRCA1 and BRCA2 (BRCA1/2) are important genes involved in homologous recombination (HR) repair, particularly in the repair of DNA double-strand breaks (DSBs) [1] . Hence, BRCA1/2, which act as tumor suppressors, suppress genetic instability [2] . From the therapeutic perspective, cancer cells with BRCA1/2 mutations are very sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors because PARP inhibitors cause an increase in DNA single-strand breaks, which are then converted to irreparable toxic DNA DSBsin those cells during replication [3] . The prevalence of BRCA1/2 mutations is highest in ovarian cancer (21%) [4] and around 5% in several other cancers, incl","cbCaipX0jmZDHlKC","https://ap.wps.com/l/cbCaipX0jmZDHlKC","pdf",6329583,18,"English","# Abstract\n## Keywords\n# 1. Introduction","[{\"question\":\"What clinical problem does the paper address regarding PARP inhibitors?\",\"answer\":\"Most BRCA1/2-mutated cancer cases eventually develop acquired resistance to PARP inhibitors. Enhancing sensitivity and preventing resistance is identified as an unmet clinical need.\"},{\"question\":\"How was PSPC1 tested as a partner to olaparib?\",\"answer\":\"The authors evaluated PSPC1 inhibition using PSPC1 small interfering RNA combined with olaparib in BRCA1/2-mutated breast and ovarian cancer cell models, and they assessed effects in a xenograft mouse model.\"},{\"question\":\"What mechanistic effects support the synergy between olaparib and PSPC1 inhibition?\",\"answer\":\"Olaparib monotherapy increased p-ATM and DNA-PKcs expression, consistent with DNA repair activation, whereas combining PSPC1 siRNA with olaparib reduced these signals, increased H2AX foci, weakened G2/M checkpoint activation, and increased apoptosis.\"}]","PSPC1 Inhibition Synergizes with Poly(ADP-ribose) Polymerase Inhibitors in a Preclinical Model of BRCA-Mutated Breast/Ovarian Cancer - Abstract, Introduction, and Keywords | PDF",1790247862,45]