{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T04:50:36Z","timestamp":1791348636892,"version":"4.3.1"},"reference-count":36,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T00:00:00Z","timestamp":1791158400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002560","name":"Soonchunhyang University","doi-asserted-by":"publisher","award":["2025-0046"],"award-info":[{"award-number":["2025-0046"]}],"id":[{"id":"10.13039\/501100002560","id-type":"DOI","asserted-by":"publisher"}]},{"award":["2025-0046"],"award-info":[{"award-number":["2025-0046"]}],"id":[{"id":"https:\/\/ror.org\/03qjsrb10","id-type":"ROR","asserted-by":"publisher"}]},{"name":"National Research Foundation (NRF) of Korea","award":["2018R1D1A1B07046129"],"award-info":[{"award-number":["2018R1D1A1B07046129"]}]},{"award":["2018R1D1A1B07046129"],"award-info":[{"award-number":["2018R1D1A1B07046129"]}],"id":[{"id":"https:\/\/ror.org\/013aysd81","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: Lactate-acclimated MSTO-211HAcT and H2452AcT malignant mesothelioma (MM) cells were previously found to tolerate gemcitabine more readily than their parental cells while remaining sensitive to apigenin. We examined whether changes in glucose metabolism and HKII contribute to the apigenin response. Methods: Apigenin was evaluated in monolayer and spheroid cultures and in a xenograft model; HKII was also silenced in the acclimated cells. Results: Apigenin reduced cell viability, p-AKT (Ser473), glycolysis-associated proteins including HKII, and mitochondrial electron transport chain proteins, while increasing p53 and markers of cell death. Tumor growth and selected metabolic proteins were reduced in the xenograft model. HKII silencing reduced cell viability and glucose utilization, lowered cellular ATP, altered mitochondrial membrane potential, and increased markers of apoptosis and necroptosis. Conclusions: HKII-associated metabolism contributes to survival of lactate-acclimated MM cells, and apigenin affects this metabolic phenotype. Direct targeting of HKII by apigenin and the complete mitochondrial apoptotic pathway require further study.<\/jats:p>","DOI":"10.3390\/nu18193276","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T10:02:27Z","timestamp":1791194547000},"page":"3276","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hexokinase II as a Potential Target of Apigenin Through the Induction of Apoptosis and Necroptosis in Malignant Mesothelioma"],"prefix":"10.3390","volume":"18","author":[{"given":"Moon-Kyun","family":"Cho","sequence":"first","affiliation":[{"name":"Department of Dermatology, Soonchunhyang University Hospital, Seoul 04401, Republic of Korea"},{"name":"Division of Molecular Cancer Research, Soonchunhyang Medical Research Institute, Soonchunhyang University, Cheonan 31511, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"}]},{"given":"Sang-Han","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Molecular Cancer Research, Soonchunhyang Medical Research Institute, Soonchunhyang University, Cheonan 31511, Republic of Korea"},{"name":"Department of Biochemistry, College of Medicine, Soonchunhyang University, Cheonan 31511, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"given":"Hae-Seon","family":"Nam","sequence":"additional","affiliation":[{"name":"Division of Molecular Cancer Research, Soonchunhyang Medical Research Institute, Soonchunhyang University, Cheonan 31511, Republic of Korea"},{"name":"Department of Tropical Medicine, College of Medicine, Soonchunhyang University, Cheonan 31511, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6364-1284","authenticated-orcid":false,"given":"Yoon-Jin","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Molecular Cancer Research, Soonchunhyang Medical Research Institute, Soonchunhyang University, Cheonan 31511, Republic of Korea"},{"name":"Department of Biochemistry, College of Medicine, Soonchunhyang University, Cheonan 31511, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,10,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Hiriart, E., Deepe, R., and Wessels, A. (2019). Mesothelium and Malignant Mesothelioma. J. Dev. Biol., 7.","DOI":"10.3390\/jdb7020007"},{"key":"ref_2","first-page":"491","article-title":"Malignant pleural mesothelioma: An epidemiological perspective","volume":"1","author":"Robinson","year":"2012","journal-title":"Ann. Cardiothorac. Surg."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1016\/S0140-6736(16)31678-6","article-title":"Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990\u20132015: A systematic analysis for the Global Burden of Disease Study 2015","volume":"388","author":"Vos","year":"2016","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1016\/S0140-6736(16)31012-1","article-title":"Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980\u20132015: A systematic analysis for the Global Burden of Disease Study 2015","volume":"388","author":"Wang","year":"2016","journal-title":"Lancet"},{"key":"ref_5","first-page":"100804","article-title":"Trends in Mesothelioma Mortality in the United States Between 1999 and 2020","volume":"6","author":"Didier","year":"2025","journal-title":"JTO Clin. Res. Rep."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"99","DOI":"10.5507\/bp.2023.008","article-title":"Current causes of mesothelioma: How has the asbestos ban changed the perspective?","volume":"167","author":"Janosikova","year":"2023","journal-title":"Biomed. Pap. Med. Fac. Palacky Univ. Olomouc"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"574","DOI":"10.21037\/tlcr.2018.04.10","article-title":"Current chemotherapy strategies in malignant pleural mesothelioma","volume":"7","author":"Baas","year":"2018","journal-title":"Transl. Lung Cancer Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1126\/science.1160809","article-title":"Understanding the Warburg effect: The metabolic requirements of cell proliferation","volume":"324","author":"Cantley","year":"2009","journal-title":"Science"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.semcancer.2022.10.004","article-title":"Reprogramming of glycolysis by chemical carcinogens during tumor development","volume":"87","author":"Shekher","year":"2022","journal-title":"Semin. Cancer Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5907","DOI":"10.1158\/0008-5472.CAN-19-1789","article-title":"A Tumor Agnostic Therapeutic Strategy for Hexokinase 1-Null\/Hexokinase 2-Positive Cancers","volume":"79","author":"Xu","year":"2019","journal-title":"Cancer Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"521","DOI":"10.21147\/j.issn.1000-9604.2019.03.14","article-title":"Hexokinase II promotes the Warburg effect by phosphorylating alpha subunit of pyruvate dehydrogenase","volume":"31","author":"Luo","year":"2019","journal-title":"Chin. J. Cancer Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3887","DOI":"10.1007\/s13277-015-4255-8","article-title":"Overexpression of Hexokinase 1 as a poor prognosticator in human colorectal cancer","volume":"37","author":"He","year":"2016","journal-title":"Tumour Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"100740","DOI":"10.1016\/j.omto.2023.100740","article-title":"Targeting the lactic acid metabolic pathway for antitumor therapy","volume":"31","author":"Li","year":"2023","journal-title":"Mol. Ther. Oncolytics"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.2967\/jnumed.107.042333","article-title":"Early prediction of response to chemotherapy and survival in malignant pleural mesothelioma using a novel semiautomated 3-dimensional volume-based analysis of serial 18F-FDG PET scans","volume":"48","author":"Francis","year":"2007","journal-title":"J. Nucl. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4587","DOI":"10.1200\/JCO.2006.06.8999","article-title":"Early response evaluation in malignant pleural mesothelioma by positron emission tomography with [18F]fluorodeoxyglucose","volume":"24","author":"Ceresoli","year":"2006","journal-title":"J. Clin. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Salehi, B., Venditti, A., Sharifi-Rad, M., Kr\u0119giel, D., Sharifi-Rad, J., Durazzo, A., Lucarini, M., Santini, A., Souto, E.B., and Novellino, E. (2019). The Therapeutic Potential of Apigenin. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20061305"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Rahmani, A.H., Alsahli, M.A., Almatroudi, A., Almogbel, M.A., Khan, A.A., Anwar, S., and Almatroodi, S.A. (2022). The Potential Role of Apigenin in Cancer Prevention and Treatment. Molecules, 27.","DOI":"10.3390\/molecules27186051"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"493","DOI":"10.4196\/kjpp.2020.24.6.493","article-title":"Apigenin causes necroptosis by inducing ROS accumulation, mitochondrial dysfunction, and ATP depletion in malignant mesothelioma cells","volume":"24","author":"Lee","year":"2020","journal-title":"Korean J. Physiol. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"111","DOI":"10.3892\/or.2023.8548","article-title":"Concurrent induction of apoptosis and necroptosis in apigenin-treated malignant mesothelioma cells: Reversal of Warburg effect through Akt inhibition and p53 upregulation","volume":"49","author":"Lee","year":"2023","journal-title":"Oncol. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.tibs.2015.12.001","article-title":"The Warburg Effect: How Does It Benefit Cancer Cells?","volume":"41","author":"Liberti","year":"2016","journal-title":"Trends Biochem. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.ccr.2013.06.014","article-title":"Hexokinase 2 is required for tumor initiation and maintenance and its systemic deletion is therapeutic in mouse models of cancer","volume":"24","author":"Patra","year":"2013","journal-title":"Cancer Cell"},{"key":"ref_22","first-page":"1452861","article-title":"The correlation of HK2 gene expression with the occurrence, immune cell infiltration, and prognosis of renal cell carcinoma","volume":"2022","author":"Liu","year":"2022","journal-title":"Dis. Markers"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.semcancer.2024.03.001","article-title":"GLUT and HK: Two primary and essential key players in tumor glycolysis","volume":"100","author":"Yadav","year":"2024","journal-title":"Semin. Cancer Biol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Ciscato, F., Ferrone, L., Masgras, I., Laquatra, C., and Rasola, A. (2021). Hexokinase 2 in Cancer: A Prima Donna Playing Multiple Characters. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22094716"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"104511","DOI":"10.1016\/j.phrs.2019.104511","article-title":"Targeting glucose metabolism to suppress cancer progression: Prospective of anti-glycolytic cancer therapy","volume":"150","author":"Mahmoud","year":"2019","journal-title":"Pharmacol. Res."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Masuelli, L., Benvenuto, M., Mattera, R., Stefano, E.D., Zago, E., Taffera, G., Tresoldi, I., Giganti, M.G., Frajese, G.V., and Berardi, G. (2017). In Vitro and In Vivo Anti-tumoral Effects of the Flavonoid Apigenin in Malignant Mesothelioma. Front. Pharmacol., 8.","DOI":"10.3389\/fphar.2017.00373"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4777","DOI":"10.1038\/sj.onc.1209603","article-title":"Hexokinase II: Cancer\u2019s double-edged sword acting as both facilitator and gatekeeper of malignancy when bound to mitochondria","volume":"25","author":"Mathupala","year":"2006","journal-title":"Oncogene"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1016\/j.yexcr.2016.11.002","article-title":"Resveratrol inhibits hexokinase II-mediated glycolysis in non-small cell lung cancer via targeting Akt signaling pathway","volume":"349","author":"Li","year":"2016","journal-title":"Exp. Cell Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/cdd.2014.173","article-title":"Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy","volume":"22","author":"Roberts","year":"2015","journal-title":"Cell Death Differ."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/j.tcb.2010.03.004","article-title":"The regulation of energy metabolism and the IGF-1\/mTOR pathways by the p53 protein","volume":"20","author":"Feng","year":"2010","journal-title":"Trends Cell Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.bbrc.2013.06.043","article-title":"p53 Regulates Glucose Metabolism by miR-34a","volume":"437","author":"Kim","year":"2013","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1533033819871306","DOI":"10.1177\/1533033819871306","article-title":"The roles of HK2 on tumorigenesis of cervical cancer","volume":"18","author":"Liu","year":"2019","journal-title":"Technol. Cancer Res. Treat."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Wu, H., Pan, L., Gao, C., Xu, H., Li, Y., Zhang, L., Ma, L., Meng, L., Sun, X., and Qin, H. (2019). Quercetin inhibits the proliferation of glycolysis-addicted HCC cells by reducing hexokinase 2 and Akt\u2013mTOR pathway. Molecules, 24.","DOI":"10.3390\/molecules24101993"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"20220726","DOI":"10.1515\/biol-2022-0726","article-title":"HK2 contributes to the proliferation, migration, and invasion of diffuse large B-cell lymphoma cells by enhancing the ERK1\/2 signaling pathway","volume":"18","author":"Zhao","year":"2023","journal-title":"Open Life Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1186\/s13046-017-0514-4","article-title":"Chrysin inhibits tumor glycolysis and induces apoptosis in hepatocellular carcinoma by targeting hexokinase-2","volume":"36","author":"Xu","year":"2017","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.hbpd.2022.09.010","article-title":"Apolipoprotein E2 inhibits mitochondrial apoptosis in pancreatic cancer cells through ERK1\/2\/CREB\/BCL-2 signaling","volume":"22","author":"Wang","year":"2023","journal-title":"Hepatobiliary Pancreat. Dis. Int."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/19\/3276\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T04:14:14Z","timestamp":1791346454000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/19\/3276"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,5]]},"references-count":36,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["nu18193276"],"URL":"https:\/\/doi.org\/10.3390\/nu18193276","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,5]]}}}