{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T21:10:44Z","timestamp":1769721044888,"version":"3.49.0"},"reference-count":41,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2023,4,6]],"date-time":"2023-04-06T00:00:00Z","timestamp":1680739200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ovarian Cancer Research Foundation (OCRF) Australia"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Eighty percent of ovarian cancer patients initially respond to chemotherapy, but the majority eventually experience a relapse and die from the disease with acquired chemoresistance. In addition, 20% of patients do not respond to treatment at all, as their disease is intrinsically chemotherapy resistant. Data-independent acquisition nano-flow liquid chromatography\u2013mass spectrometry (DIA LC-MS) identified the three protein markers: gelsolin (GSN), calmodulin (CALM1), and thioredoxin (TXN), to be elevated in high-grade serous ovarian cancer (HGSOC) tissues from patients that responded to chemotherapy compared to those who did not; the differential expression of the three protein markers was confirmed by immunohistochemistry. Analysis of the online GENT2 database showed that mRNA levels of GSN, CALM1, and TXN were decreased in HGSOC compared to fallopian tube epithelium. Elevated levels of GSN and TXN mRNA expression correlated with increased overall and progression-free survival, respectively, in a Kaplan\u2013Meier analysis of a large online repository of HGSOC patient data. Importantly, differential expression of the three protein markers was further confirmed when comparing parental OVCAR-5 cells to carboplatin-resistant OVCAR-5 cells using DIA LC-MS analysis. Our findings suggest that GSN, CALM1, and TXN may be useful biomarkers for predicting chemotherapy response and understanding the mechanisms of chemotherapy resistance. Proteomic data are available via ProteomeXchange with identifier PXD033785.<\/jats:p>","DOI":"10.3390\/cancers15072172","type":"journal-article","created":{"date-parts":[[2023,4,6]],"date-time":"2023-04-06T03:59:55Z","timestamp":1680753595000},"page":"2172","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Label-Free Quantification Mass Spectrometry Identifies Protein Markers of Chemotherapy Response in High-Grade Serous Ovarian Cancer"],"prefix":"10.3390","volume":"15","author":[{"given":"Georgia","family":"Arentz","sequence":"first","affiliation":[{"name":"Adelaide Proteomics Centre, School of Biological Sciences, The University of Adelaide, Adelaide, SA 5005, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Parul","family":"Mittal","sequence":"additional","affiliation":[{"name":"Clinical & Health Sciences, University of South Australia, Adelaide, SA 5001, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manuela","family":"Klingler-Hoffmann","sequence":"additional","affiliation":[{"name":"Clinical & Health Sciences, University of South Australia, Adelaide, SA 5001, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark R.","family":"Condina","sequence":"additional","affiliation":[{"name":"Future Industries Institute, Mawson Lakes Campus, University of South Australia, Mawson Lakes, SA 5095, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7415-1854","authenticated-orcid":false,"given":"Carmela","family":"Ricciardelli","sequence":"additional","affiliation":[{"name":"Discipline of Obstetrics and Gynecology, Adelaide Medical School, Robinson Research Institute, University of Adelaide, Adelaide, SA 5000, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2071-5308","authenticated-orcid":false,"given":"Noor A.","family":"Lokman","sequence":"additional","affiliation":[{"name":"Discipline of Obstetrics and Gynecology, Adelaide Medical School, Robinson Research Institute, University of Adelaide, Adelaide, SA 5000, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6232-5703","authenticated-orcid":false,"given":"Gurjeet","family":"Kaur","sequence":"additional","affiliation":[{"name":"Institute for Research in Molecular Medicine, University Sains Malaysia, Minden 11800, Pulau Pinang, Malaysia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin K.","family":"Oehler","sequence":"additional","affiliation":[{"name":"Discipline of Obstetrics and Gynecology, Adelaide Medical School, Robinson Research Institute, University of Adelaide, Adelaide, SA 5000, Australia"},{"name":"Department of Gynecological Oncology, Royal Adelaide Hospital, Adelaide, SA 5005, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Hoffmann","sequence":"additional","affiliation":[{"name":"Clinical & Health Sciences, University of South Australia, Adelaide, SA 5001, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,6]]},"reference":[{"key":"ref_1","unstructured":"Fund, W.C.R. (2023, January 05). Ovarian Cancer Statistics. Available online: https:\/\/www.wcrf.org\/cancer-trends\/ovarian-cancer-statistics\/."},{"key":"ref_2","unstructured":"Australian Institute of Health and Welfare (2023, January 05). Ovarian Cancer Statistics in Australia, Available online: https:\/\/www.canceraustralia.gov.au\/cancer-types\/ovarian-cancer\/statistics."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/j.maturitas.2009.01.001","article-title":"Diverse molecular pathways in ovarian cancer and their clinical significance","volume":"62","author":"Ricciardelli","year":"2009","journal-title":"Maturitas"},{"key":"ref_4","first-page":"3695","article-title":"The HE4 (WFDC2) protein is a biomarker for ovarian carcinoma","volume":"63","author":"Raycraft","year":"2003","journal-title":"Cancer Res."},{"key":"ref_5","first-page":"1727","article-title":"A mathematic model for relating the drug sensitivity of tumors to their spontaneous mutation rate","volume":"63","author":"Goldie","year":"1979","journal-title":"Cancer Treat. Rep."},{"key":"ref_6","unstructured":"American Cancer Society, and The American Cancer Society Medical and Editorial Content Team (2023, January 05). Treatment of Invasive Epithelial Ovarian Cancers, by Stage. Available online: https:\/\/www.cancer.org\/cancer\/ovarian-cancer\/treating\/by-stage.html#written_by."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.1016\/S0959-8049(98)00230-5","article-title":"Pharmacogenetics and cancer chemotherapy","volume":"34","author":"Iyer","year":"1998","journal-title":"Eur. J. Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.ygyno.2014.10.010","article-title":"Contemporary phase III clinical trial endpoints in advanced ovarian cancer: Assessing the pros and cons of objective response rate, progression-free survival, and overall survival","volume":"136","year":"2015","journal-title":"Gynecol. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1634\/theoncologist.5-1-26","article-title":"Second-line treatment of ovarian cancer","volume":"5","author":"Markman","year":"2000","journal-title":"Oncologist"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"vii218","DOI":"10.1093\/annonc\/mdq377","article-title":"Optimal treatment for relapsing ovarian cancer","volume":"21","author":"Ledermann","year":"2010","journal-title":"Ann. Oncol."},{"key":"ref_11","unstructured":"Foley, O.W., Rauh-Hain, J.A., and del Carmen, M.G. (2013). Recurrent epithelial ovarian cancer: An update on treatment. Oncology, 27."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Sharma, S., Michael, H.N., Federica, D.N., Louise, A.K., Pauline, A.W., Stuart, J.M., Bernard, R.H., Alan, L., Richard, O., and Andrew, C.H. (2003). Outcome of ATP-based tumor chemosensitivity assay directed chemotherapy in heavily pre-treated recurrent ovarian carcinoma. BMC Cancer, 3.","DOI":"10.1186\/1471-2407-3-19"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"86","DOI":"10.3389\/fncel.2015.00086","article-title":"Cancer as a channelopathy: Ion channels and pumps in tumor development and progression","volume":"9","author":"Litan","year":"2015","journal-title":"Front. Cell Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Roy, L., and Cowden Dahl, K.D. (2018). Can Stemness and Chemoresistance Be Therapeutically Targeted via Signaling Pathways in Ovarian Cancer?. Cancers, 10.","DOI":"10.20944\/preprints201806.0262.v1"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1016\/j.gendis.2020.11.017","article-title":"Revisiting chemoresistance in ovarian cancer: Mechanism, biomarkers, and precision medicine","volume":"9","author":"Guo","year":"2022","journal-title":"Genes Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.semcancer.2021.08.005","article-title":"Platinum-resistant ovarian cancer: From drug resistance mechanisms to liquid biopsy-based biomarkers for disease management","volume":"77","author":"Khan","year":"2021","journal-title":"Semin. Cancer Biol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Acland, M., Lokman, N.A., Young, C., Anderson, D., Condina, M., Desire, C., Noye, T.M., Wang, W., Ricciardelli, C., and Creek, D.J. (2022). Chemoresistant Cancer Cell Lines Are Characterized by Migratory, Amino Acid Metabolism, Protein Catabolism and IFN1 Signalling Perturbations. Cancers, 14.","DOI":"10.3390\/cancers14112763"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Park, S.-J., Yoon, B.-H., and Kim, S.-Y. (2019). GENT2: An updated gene expression database for normal and tumor tissues. BMC Med. Genom., 12.","DOI":"10.1186\/s12920-019-0514-7"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1021\/pr300996x","article-title":"Tryptic Peptide Reference Data Sets for MALDI Imaging Mass Spectrometry on Formalin-fixed Ovarian Cancer Tissues","volume":"12","author":"Meding","year":"2012","journal-title":"J. Proteome Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1793","DOI":"10.1002\/pmic.201500455","article-title":"Lymph node metastasis of primary endometrial cancers: Associated proteins revealed by MALDI imaging","volume":"16","author":"Mittal","year":"2016","journal-title":"Proteomics"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Acland, M., Mittal, P., Arentz, G., Whitehead, F., Hoffmann, P., Klingler-Hoffmann, M., and Oehler, M.K. (2022). A Protocol for the Acquisition of Comprehensive Proteomics Data from Single Cases Using Formalin-Fixed Paraffin Embedded Sections. Methods Protoc., 5.","DOI":"10.3390\/mps5040057"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Ricciardelli, C., Ween, M.P., Lokman, N.A., Tan, I.A., Pyragius, C.E., and Oehler, M.K. (2013). Chemotherapy-induced hyaluronan production: A novel chemoresistance mechanism in ovarian cancer. BMC Cancer, 13.","DOI":"10.1186\/1471-2407-13-476"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1038\/nmeth.1322","article-title":"Universal sample preparation method for proteome analysis","volume":"6","author":"Wisniewski","year":"2009","journal-title":"Nat. Methods"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1794","DOI":"10.1021\/pr101065j","article-title":"Andromeda: A Peptide Search Engine Integrated into the MaxQuant Environment","volume":"10","author":"Cox","year":"2011","journal-title":"J. Proteome Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1093\/bioinformatics\/btq054","article-title":"Skyline: An open source document editor for creating and analyzing targeted proteomics experiments","volume":"26","author":"MacLean","year":"2010","journal-title":"Bioinformatics"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1016\/j.bbapap.2016.10.010","article-title":"Annexin A2 and alpha actinin 4 expression correlates with metastatic potential of primary endometrial cancer","volume":"1865","author":"Mittal","year":"2017","journal-title":"Biochim. Biophys. Acta Proteins Proteom."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Varghese, F., Bukhari, A.B., Malhotra, R., and De, A. (2014). IHC Profiler: An Open Source Plugin for the Quantitative Evaluation and Automated Scoring of Immunohistochemistry Images of Human Tissue Samples. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0096801"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1530\/ERC-11-0329","article-title":"Implementing an online tool for genome-wide validation of survival-associated biomarkers in ovarian-cancer using microarray data from 1287 patients","volume":"19","author":"Gyorffy","year":"2012","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1002\/path.2091","article-title":"A candidate precursor to serous carcinoma that originates in the distal fallopian tube","volume":"211","author":"Lee","year":"2007","journal-title":"J. Pathol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.canlet.2020.02.017","article-title":"Fallopian tube initiation of high grade serous ovarian cancer and ovarian metastasis: Mechanisms and therapeutic implications","volume":"476","author":"Bergsten","year":"2020","journal-title":"Cancer Lett."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4965","DOI":"10.3892\/ol.2017.6096","article-title":"Comparative secretome of ovarian serous carcinoma: Gelsolin in the spotlight","volume":"13","author":"Pierredon","year":"2017","journal-title":"Oncol. Lett."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"14442","DOI":"10.1073\/pnas.1401166111","article-title":"Cell fate regulation by gelsolin in human gynecologic cancers","volume":"111","author":"Abedini","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"100502","DOI":"10.1016\/j.mcpro.2023.100502","article-title":"Proteomic Discovery of Plasma Protein Biomarkers and Development of Models Predicting Prognosis of High-Grade Serous Ovarian Carcinoma","volume":"22","author":"Kim","year":"2023","journal-title":"Mol. Cell. Proteom."},{"key":"ref_34","first-page":"1600","article-title":"The exosome-mediated autocrine and paracrine actions of plasma gelsolin in ovarian cancer chemoresistance","volume":"39","author":"Nakka","year":"2019","journal-title":"Oncogene"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"25308","DOI":"10.18632\/oncotarget.4490","article-title":"Calmodulin antagonists promote TRA-8 therapy of resistant pancreatic cancer","volume":"6","author":"Yuan","year":"2015","journal-title":"Oncotarget"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1016\/j.bbadis.2014.12.002","article-title":"Thioredoxin 1 upregulates FOXO1 transcriptional activity in drug resistance in ovarian cancer cells","volume":"1852","author":"Wang","year":"2015","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"604","DOI":"10.3109\/1354750X.2014.956793","article-title":"Thioredoxin 1 as a serum marker for ovarian cancer and its use in combination with CA125 for improving the sensitivity of ovarian cancer diagnoses","volume":"19","author":"Park","year":"2014","journal-title":"Biomarkers"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Criscuolo, D., Avolio, R., Parri, M., Romano, S., Chiarugi, P., Matassa, D.S., and Esposito, F. (2022). Decreased Levels of GSH Are Associated with Platinum Resistance in High-Grade Serous Ovarian Cancer. Antioxidants, 11.","DOI":"10.3390\/antiox11081544"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1158\/1535-7163.MCT-11-0599","article-title":"The Relationship of Thioredoxin-1 and Cisplatin Resistance: Its Impact on ROS and Oxidative Metabolism in Lung Cancer Cells","volume":"11","author":"Wangpaichitr","year":"2012","journal-title":"Mol. Cancer Ther."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"6395","DOI":"10.1038\/s41388-021-02055-2","article-title":"A highly annotated database of genes associated with platinum resistance in cancer","volume":"40","author":"Huang","year":"2021","journal-title":"Oncogene"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"D442","DOI":"10.1093\/nar\/gky1106","article-title":"The PRIDE database and related tools and resources in 2019: Improving support for quantification data","volume":"47","author":"Csordas","year":"2019","journal-title":"Nucleic Acids Res."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/15\/7\/2172\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:10:54Z","timestamp":1760123454000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/15\/7\/2172"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,6]]},"references-count":41,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2023,4]]}},"alternative-id":["cancers15072172"],"URL":"https:\/\/doi.org\/10.3390\/cancers15072172","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,6]]}}}