{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T03:25:41Z","timestamp":1784690741131,"version":"3.55.0"},"reference-count":65,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,6,8]],"date-time":"2025-06-08T00:00:00Z","timestamp":1749340800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005972","name":"Deutsche Krebshilfe","doi-asserted-by":"publisher","award":["70116875"],"award-info":[{"award-number":["70116875"]}],"id":[{"id":"10.13039\/501100005972","id-type":"DOI","asserted-by":"publisher"}]},{"name":"German Cancer Consortium (DKTK), Heidelberg","award":["70116875"],"award-info":[{"award-number":["70116875"]}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: Death-associated protein kinase 1 (DAPK1) is a serine\/threonine kinase that plays a crucial role in cancer by regulating apoptosis through interactions with TP53. Aberrant expression of DAPK1 was shown in certain types of human cancer contributing to tumor progression and chemoresistance. This study aimed to investigate the role of DAPK1 in high-grade serous ovarian cancer (HGSOC) and to evaluate the therapeutic potential of restoring its kinase activity, including the use of truncated DAPK1 variants, to overcome chemoresistance and enhance tumor suppression. Methods: Gene expression analysis was performed on ovarian cancer tissues compared to benign controls to assess DAPK1 downregulation and its epigenetic regulation. Prognostic relevance was evaluated in a cohort of 1436 HGSOC patient samples. Functional restoration of DAPK1 was conducted in HGSOC cell lines and patient-derived primary tumor cells using vector-based expression or in vitro-transcribed (IVT) DAPK1 mRNA, including the application of truncated DAPK1 (\u0394DAPK1) forms. To assess apoptosis, Caspase activation assays, 2D-colony formation assays, and cell survival assays were performed. To analyze the reactivation of DAPK1 downstream signaling, phosphorylation of p53 at Ser20 and the expression of p53 target proteins were examined. Chemosensitivity to Paclitaxel and Cisplatin was quantified by changes in IC50 values. Results: DAPK1 expression was significantly downregulated in ovarian cancer compared to benign tissue, correlating with epigenetic silencing, and showed prognostic value in early-stage HGSOC. Restoration of DAPK1 activity, including \u0394DAPK1 variants, led to phosphorylation of p53 Ser20, increased expression of p53 target proteins, and Caspase-dependent apoptosis. Reactivation of DAPK1 sensitized both established HGSOC cell lines and patient-derived ascites cells to Paclitaxel and Cisplatin. These effects occurred through both p53-dependent and p53-independent pathways, enabling robust tumor suppression even in p53-mutant contexts. Conclusions: Reactivation of DAPK1, particularly through truncated variants, represents a promising therapeutic strategy to overcome chemoresistance in HGSOC. The dual mechanisms of tumor suppression provide a strong rationale for developing DAPK1-based therapies to enhance the efficacy of standard chemotherapy, especially in patients with chemoresistant or p53-deficient tumors. Future work should focus on optimizing delivery approaches for DAPK1 variants and assessing their synergistic potential with emerging targeted treatments in clinical settings.<\/jats:p>","DOI":"10.3390\/cancers17121910","type":"journal-article","created":{"date-parts":[[2025,6,9]],"date-time":"2025-06-09T04:23:02Z","timestamp":1749442982000},"page":"1910","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Truncated DAPK Variants Restore Tumor Suppressor Activity and Synergize with Standard Therapies in High-Grade Serous Ovarian Cancer"],"prefix":"10.3390","volume":"17","author":[{"given":"Monika","family":"Raab","sequence":"first","affiliation":[{"name":"Department of Gynecology, Medical School, Goethe-University, 60596 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1874-0341","authenticated-orcid":false,"given":"Khayal","family":"Gasimli","sequence":"additional","affiliation":[{"name":"Department of Gynecology, Medical School, Goethe-University, 60596 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5772-3766","authenticated-orcid":false,"given":"Bal\u00e1zs","family":"Gy\u0151rffy","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics, Semmelweis University, 1094 Budapest, Hungary"},{"name":"Department of Biophysics, Medical School, University of Pecs, 7624 Pecs, Hungary"},{"name":"HUN-REN TTK Cancer Biomarker Research Group, 1117 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3847-1353","authenticated-orcid":false,"given":"Samuel","family":"Pe\u00f1a-Llopis","sequence":"additional","affiliation":[{"name":"Translational Genomics, Department of Ophthalmology, University Hospital Essen, 45147 Essen, Germany"},{"name":"German Cancer Consortium (DKTK) at the University Hospital Essen and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sven","family":"Becker","sequence":"additional","affiliation":[{"name":"Department of Gynecology, Medical School, Goethe-University, 60596 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8202-0694","authenticated-orcid":false,"given":"Mourad","family":"Sanhaji","sequence":"additional","affiliation":[{"name":"Department of Gynecology, Medical School, Goethe-University, 60596 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus","family":"Strebhardt","sequence":"additional","affiliation":[{"name":"Department of Gynecology, Medical School, Goethe-University, 60596 Frankfurt am Main, Germany"},{"name":"German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2451","DOI":"10.1002\/ijc.30676","article-title":"International patterns and trends in ovarian cancer incidence, overall and by histologic subtype","volume":"140","author":"Coburn","year":"2017","journal-title":"Int. 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