{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T09:21:47Z","timestamp":1790760107112,"version":"4.1.0"},"reference-count":52,"publisher":"Springer Science and Business Media LLC","issue":"8","license":[{"start":{"date-parts":[[2023,8,1]],"date-time":"2023-08-01T00:00:00Z","timestamp":1690848000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,8,1]],"date-time":"2023-08-01T00:00:00Z","timestamp":1690848000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>With technological advancements, radiotherapy (RT) has become an effective non-surgical treatment for hepatocellular carcinoma (HCC), comprehensively improving the local control rate of patients with HCC. However, some patients with HCC still experience radio-resistance, cancer recurrence, and distant metastasis following RT. Our previous study has revealed that hexokinase 2 (HK2), a potent oncogene, was overexpressed in radio-resistant HCC cell lines; however, its role in HCC radio-resistance remains elusive. Here, we confirmed the upregulation of HK2 in HCC tissue, which is related to unfavorable prognosis in patients with HCC, and demonstrated that HK2 exerts a radio-resistant role by attenuating apoptosis and promoting proliferation in HCC cell lines. HK2 downregulation combined with ionizing radiation showed an excellent synergistic lethal effect. Mechanistically, HK2 alleviated ionizing radiation-mediated apoptosis by complexing with pro-apoptotic protein aminoacyl tRNA synthetase complex interacting multifunctional protein 2 (AIMP2) while enhancing its autophagic lysosomal-dependent degradation, thereby increasing radio-resistance of HCC. Pharmacologically, ketoconazole, an FDA-approved antifungal drug, served as an inhibitor of HK2 and synergistically enhanced the efficacy of RT. Our results indicated that HK2 played a vital role in radio-resistance and could be a potential therapeutic target for improving RT efficacy in HCC.<\/jats:p>","DOI":"10.1038\/s41419-023-06009-2","type":"journal-article","created":{"date-parts":[[2023,8,1]],"date-time":"2023-08-01T03:33:54Z","timestamp":1690860834000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Hexokinase 2 confers radio-resistance in hepatocellular carcinoma by promoting autophagy-dependent degradation of AIMP2"],"prefix":"10.1038","volume":"14","author":[{"given":"Yilin","family":"Zheng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5079-6129","authenticated-orcid":false,"given":"Yizhi","family":"Zhan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuqin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaowei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuwen","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yining","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junying","family":"Qian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1775-6923","authenticated-orcid":false,"given":"Yanqing","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5035-9255","authenticated-orcid":false,"given":"Yi","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0483-2237","authenticated-orcid":false,"given":"Yuan","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,8,1]]},"reference":[{"key":"6009_CR1","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1038\/s41572-020-00240-3","volume":"7","author":"JM Llovet","year":"2021","unstructured":"Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021;7:6.","journal-title":"Nat Rev Dis Primers"},{"key":"6009_CR2","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.drup.2010.01.002","volume":"13","author":"M Verheij","year":"2010","unstructured":"Verheij M, Vens C, van Triest B. Novel therapeutics in combination with radiotherapy to improve cancer treatment: rationale, mechanisms of action and clinical perspective. Drug Resist Updat. 2010;13:29\u201343.","journal-title":"Drug Resist Updat"},{"key":"6009_CR3","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.radonc.2019.12.004","volume":"145","author":"J Lee","year":"2020","unstructured":"Lee J, Shin I, Yoon WS, Koom WS, Rim CH. Comparisons between radiofrequency ablation and stereotactic body radiotherapy for liver malignancies: meta-analyses and a systematic review. Radiother Oncol. 2020;145:63\u201370.","journal-title":"Radiother Oncol"},{"key":"6009_CR4","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1038\/s41575-019-0247-2","volume":"17","author":"AM Buckley","year":"2020","unstructured":"Buckley AM, Lynam-Lennon N, O\u2019Neill H, O\u2019Sullivan J. Targeting hallmarks of cancer to enhance radiosensitivity in gastrointestinal cancers. Nat Rev Gastroenterol Hepatol. 2020;17:298\u2013313.","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"6009_CR5","doi-asserted-by":"publisher","first-page":"1216","DOI":"10.1016\/j.cell.2013.11.019","volume":"155","author":"JY Guo","year":"2013","unstructured":"Guo JY, Xia B, White E. Autophagy-mediated tumor promotion. Cell. 2013;155:1216\u20139.","journal-title":"Cell"},{"key":"6009_CR6","doi-asserted-by":"publisher","first-page":"442","DOI":"10.4161\/auto.5.4.7667","volume":"5","author":"CE Zois","year":"2009","unstructured":"Zois CE, Koukourakis MI. Radiation-induced autophagy in normal and cancer cells: towards novel cytoprotection and radio-sensitization policies? Autophagy. 2009;5:442\u201350.","journal-title":"Autophagy"},{"key":"6009_CR7","doi-asserted-by":"publisher","first-page":"1485","DOI":"10.1158\/0008-5472.CAN-07-0562","volume":"68","author":"A Apel","year":"2008","unstructured":"Apel A, Herr I, Schwarz H, Rodemann HP, Mayer A. Blocked autophagy sensitizes resistant carcinoma cells to radiation therapy. Cancer Res. 2008;68:1485\u201394.","journal-title":"Cancer Res"},{"key":"6009_CR8","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/j.cmet.2020.12.015","volume":"33","author":"D Xu","year":"2021","unstructured":"Xu D, Shao F, Bian X, Meng Y, Liang T, Lu Z. The evolving landscape of noncanonical functions of metabolic enzymes in cancer and other pathologies. Cell Metab. 2021;33:33\u201350.","journal-title":"Cell Metab"},{"key":"6009_CR9","first-page":"2247","volume":"42","author":"L Fan","year":"2018","unstructured":"Fan L, Huang C, Li J, Gao T, Lin Z, Yao T. Long noncoding rna urothelial cancer associated 1 regulates radioresistance via the hexokinase 2\/glycolytic pathway in cervical cancer. Int J Mol Med. 2018;42:2247\u201359.","journal-title":"Int J Mol Med"},{"key":"6009_CR10","doi-asserted-by":"publisher","first-page":"5881","DOI":"10.1158\/1078-0432.CCR-17-1151","volume":"23","author":"V Gunda","year":"2017","unstructured":"Gunda V, Souchek J, Abrego J, Shukla SK, Goode GD, Vernucci E, et al. Muc1-mediated metabolic alterations regulate response to radiotherapy in pancreatic cancer. Clin Cancer Res. 2017;23:5881\u201391.","journal-title":"Clin Cancer Res"},{"key":"6009_CR11","doi-asserted-by":"publisher","first-page":"1794","DOI":"10.1158\/1535-7163.MCT-15-0247","volume":"14","author":"H Shen","year":"2015","unstructured":"Shen H, Hau E, Joshi S, Dilda PJ, Mcdonald KL. Sensitization of glioblastoma cells to irradiation by modulating the glucose metabolism. Mol Cancer Ther. 2015;14:1794\u2013804.","journal-title":"Mol Cancer Ther"},{"key":"6009_CR12","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1186\/s13046-020-01629-4","volume":"39","author":"J Feng","year":"2020","unstructured":"Feng J, Li J, Wu L, Yu Q, Ji J, Wu J, et al. Emerging roles and the regulation of aerobic glycolysis in hepatocellular carcinoma. J Exp Clin Cancer Res. 2020;39:126.","journal-title":"J Exp Clin Cancer Res"},{"issue":"6","key":"6009_CR13","doi-asserted-by":"publisher","first-page":"1386","DOI":"10.1002\/hep.32177","volume":"75","author":"Y Fang","year":"2022","unstructured":"Fang Y, Zhan Y, Xie Y, Du S, Chen Y, Zeng Z, et al. Integration of glucose and cardiolipin anabolism confers radiation resistance of hcc. Hepatology. 2022;75(6):1386\u20131401.","journal-title":"Hepatology"},{"key":"6009_CR14","doi-asserted-by":"publisher","first-page":"1312","DOI":"10.1016\/j.cmet.2022.08.002","volume":"34","author":"D Guo","year":"2022","unstructured":"Guo D, Tong Y, Jiang X, Meng Y, Jiang H, Du L, et al. Aerobic glycolysis promotes tumor immune evasion by hexokinase2-mediated phosphorylation of ikappabalpha. Cell Metab. 2022;34:1312\u201324.","journal-title":"Cell Metab"},{"key":"6009_CR15","doi-asserted-by":"publisher","first-page":"3422","DOI":"10.1158\/0008-5472.CAN-15-3255","volume":"76","author":"DG Kim","year":"2016","unstructured":"Kim DG, Lee JY, Lee JH, Cho HY, Kang BS, Jang SY, et al. Oncogenic mutation of aimp2\/p38 inhibits its tumor-suppressive interaction with smurf2. Cancer Res. 2016;76:3422\u201336.","journal-title":"Cancer Res"},{"key":"6009_CR16","doi-asserted-by":"publisher","first-page":"4559","DOI":"10.1158\/0008-5472.CAN-15-3357","volume":"76","author":"MK Yum","year":"2016","unstructured":"Yum MK, Kang J, Lee A, Jo Y, Seo J, Kim H, et al. Aimp2 controls intestinal stem cell compartments and tumorigenesis by modulating wnt\/\u03b2-catenin signaling. Cancer Res. 2016;76:4559\u201368.","journal-title":"Cancer Res"},{"key":"6009_CR17","doi-asserted-by":"publisher","first-page":"659","DOI":"10.1158\/1078-0432.CCR-17-0352","volume":"24","author":"Q Zhong","year":"2018","unstructured":"Zhong Q, Liu Z, Lin Z, Hu Z, Yuan L, Liu Y, et al. Therars\u2013mad1l1 fusion gene induces cancer stem cell\u2013like properties and therapeutic resistance in nasopharyngeal carcinoma. Clin Cancer Res. 2018;24:659\u201373.","journal-title":"Clin Cancer Res"},{"key":"6009_CR18","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1016\/j.tem.2019.04.011","volume":"30","author":"N Rabbani","year":"2019","unstructured":"Rabbani N, Thornalley PJ. Hexokinase-2 glycolytic overload in diabetes and ischemia-reperfusion injury. Trends Endocrinol Metab. 2019;30:419\u201331.","journal-title":"Trends Endocrinol Metab"},{"key":"6009_CR19","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-11662-3","volume":"10","author":"Y Fang","year":"2019","unstructured":"Fang Y, Shen ZY, Zhan YZ, Feng XC, Chen KL, Li YS, et al. Cd36 inhibits beta-catenin\/c-myc-mediated glycolysis through ubiquitination of gpc4 to repress colorectal tumorigenesis. Nat Commun. 2019;10:3981.","journal-title":"Nat Commun"},{"key":"6009_CR20","doi-asserted-by":"publisher","first-page":"5330","DOI":"10.1158\/0008-5472.CAN-20-2425","volume":"80","author":"K Tateishi","year":"2020","unstructured":"Tateishi K, Miyake Y, Kawazu M, Sasaki N, Nakamura T, Sasame J, et al. A hyperactive rela\/p65-hexokinase 2 signaling axis drives primary central nervous system lymphoma. Cancer Res. 2020;80:5330\u201343.","journal-title":"Cancer Res"},{"key":"6009_CR21","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1016\/j.ebiom.2016.03.022","volume":"7","author":"L Wang","year":"2016","unstructured":"Wang L, Wang J, Xiong H, Wu F, Lan T, Zhang Y, et al. Co-targeting hexokinase 2-mediated warburg effect and ulk1-dependent autophagy suppresses tumor growth of pten- and tp53-deficiency-driven castration-resistant prostate cancer. EBioMedicine. 2016;7:50\u201361.","journal-title":"EBioMedicine"},{"key":"6009_CR22","doi-asserted-by":"publisher","first-page":"2710","DOI":"10.1242\/jcs.049767","volume":"122","author":"JW Choi","year":"2009","unstructured":"Choi JW, Kim DG, Park MC, Um JY, Han JM, Park SG, et al. Aimp2 promotes tnfalpha-dependent apoptosis via ubiquitin-mediated degradation of traf2. J Cell Sci. 2009;122:2710\u20135.","journal-title":"J Cell Sci"},{"key":"6009_CR23","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1093\/jmcb\/mjs018","volume":"4","author":"JW Choi","year":"2012","unstructured":"Choi JW, Lee JW, Kim JK, Jeon HK, Choi JJ, Kim DG, et al. Splicing variant of aimp2 as an effective target against chemoresistant ovarian cancer. J Mol Cell Biol. 2012;4:164\u201373.","journal-title":"J Mol Cell Biol"},{"key":"6009_CR24","doi-asserted-by":"publisher","first-page":"844","DOI":"10.1158\/1078-0432.CCR-18-1854","volume":"25","author":"S Agnihotri","year":"2019","unstructured":"Agnihotri S, Mansouri S, Burrell K, Li M, Mamatjan Y, Liu J, et al. Ketoconazole and posaconazole selectively target hk2-expressing glioblastoma cells. Clin Cancer Res. 2019;25:844\u201355.","journal-title":"Clin Cancer Res"},{"key":"6009_CR25","doi-asserted-by":"publisher","first-page":"m3544","DOI":"10.1136\/bmj.m3544","volume":"371","author":"JD Yang","year":"2020","unstructured":"Yang JD, Heimbach JK. New advances in the diagnosis and management of hepatocellular carcinoma. BMJ. 2020;371:m3544.","journal-title":"BMJ"},{"key":"6009_CR26","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1016\/j.radonc.2018.12.005","volume":"131","author":"CH Rim","year":"2019","unstructured":"Rim CH, Kim HJ, Seong J. Clinical feasibility and efficacy of stereotactic body radiotherapy for hepatocellular carcinoma: a systematic review and meta-analysis of observational studies. Radiother Oncol. 2019;131:135\u201344.","journal-title":"Radiother Oncol"},{"key":"6009_CR27","doi-asserted-by":"publisher","first-page":"4716","DOI":"10.3390\/ijms22094716","volume":"22","author":"F Ciscato","year":"2021","unstructured":"Ciscato F, Ferrone L, Masgras I, Laquatra C, Rasola A. Hexokinase 2 in cancer: a prima donna playing multiple characters. Int J Mol Sci. 2021;22:4716.","journal-title":"Int J Mol Sci"},{"key":"6009_CR28","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-02733-4","volume":"9","author":"D Dewaal","year":"2018","unstructured":"Dewaal D, Nogueira V, Terry AR, Patra KC, Jeon SM, Guzman G, et al. Antoniewicz MR, Hay N. Hexokinase-2 depletion inhibits glycolysis and induces oxidative phosphorylation in hepatocellular carcinoma and sensitizes to metformin. Nat Commun. 2018;9:446.","journal-title":"Nat Commun"},{"key":"6009_CR29","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-019-0947-9","volume":"18","author":"J Chen","year":"2019","unstructured":"Chen J, Yu Y, Li H, Hu Q, Chen X, He Y, et al. Long non-coding rna pvt1 promotes tumor progression by regulating the mir-143\/hk2 axis in gallbladder cancer. Mol Cancer. 2019;18:33.","journal-title":"Mol Cancer"},{"key":"6009_CR30","doi-asserted-by":"publisher","first-page":"872","DOI":"10.1038\/s41556-022-00925-9","volume":"24","author":"GE Thomas","year":"2022","unstructured":"Thomas GE, Egan G, Garcia-Prat L, Botham A, Voisin V, Patel PS, et al. The metabolic enzyme hexokinase 2 localizes to the nucleus in aml and normal haematopoietic stem and progenitor cells to maintain stemness. Nat Cell Biol. 2022;24:872\u201384.","journal-title":"Nat Cell Biol"},{"key":"6009_CR31","doi-asserted-by":"crossref","unstructured":"Fan T, Sun G, Sun X, Zhao L, Zhong R, Peng Y. Tumor energy metabolism and potential of 3-bromopyruvate as an inhibitor of aerobic glycolysis: implications in tumor treatment. Cancers. 2019;11:317.","DOI":"10.3390\/cancers11030317"},{"key":"6009_CR32","doi-asserted-by":"crossref","unstructured":"Huang Y, Sun G, Sun X, Li F, Zhao L, Zhong R, et al. The potential of lonidamine in combination with chemotherapy and physical therapy in cancer treatment. Cancers. 2020;12:3332.","DOI":"10.3390\/cancers12113332"},{"key":"6009_CR33","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.semcancer.2017.12.003","volume":"56","author":"MH Baig","year":"2019","unstructured":"Baig MH, Adil M, Khan R, Dhadi S, Ahmad K, Rabbani G, et al. Enzyme targeting strategies for prevention and treatment of cancer: implications for cancer therapy. Semin Cancer Biol. 2019;56:1\u201311.","journal-title":"Semin Cancer Biol"},{"key":"6009_CR34","doi-asserted-by":"publisher","first-page":"115029","DOI":"10.1016\/j.bcp.2022.115029","volume":"199","author":"X Sun","year":"2022","unstructured":"Sun X, Fan T, Sun G, Zhou Y, Huang Y, Zhang N, et al. 2-deoxy-d-glucose increases the sensitivity of glioblastoma cells to bcnu through the regulation of glycolysis, ros and ers pathways: in vitro and in vivo validation. Biochem Pharmacol. 2022;199:115029.","journal-title":"Biochem Pharmacol"},{"key":"6009_CR35","doi-asserted-by":"publisher","first-page":"113988","DOI":"10.1016\/j.bcp.2020.113988","volume":"177","author":"X Sun","year":"2020","unstructured":"Sun X, Sun G, Huang Y, Hao Y, Tang X, Zhang N, et al. 3-bromopyruvate regulates the status of glycolysis and bcnu sensitivity in human hepatocellular carcinoma cells. Biochem Pharmacol. 2020;177:113988.","journal-title":"Biochem Pharmacol"},{"key":"6009_CR36","doi-asserted-by":"publisher","first-page":"152413","DOI":"10.1016\/j.tox.2020.152413","volume":"435","author":"X Sun","year":"2020","unstructured":"Sun X, Sun G, Huang Y, Zhang S, Tang X, Zhang N, et al. Glycolytic inhibition by 3-bromopyruvate increases the cytotoxic effects of chloroethylnitrosoureas to human glioma cells and the dna interstrand cross-links formation. Toxicology. 2020;435:152413.","journal-title":"Toxicology"},{"key":"6009_CR37","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1038\/s42003-021-01749-3","volume":"4","author":"L Perrin-Cocon","year":"2021","unstructured":"Perrin-Cocon L, Vidalain PO, Jacquemin C, Aublin-Gex A, Olmstead K, Panthu B, et al. A hexokinase isoenzyme switch in human liver cancer cells promotes lipogenesis and enhances innate immunity. Commun Biol. 2021;4:217.","journal-title":"Commun Biol"},{"key":"6009_CR38","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1126\/science.aaf6284","volume":"354","author":"M Peng","year":"2016","unstructured":"Peng M, Yin N, Chhangawala S, Xu K, Leslie CS, Li MO. Aerobic glycolysis promotes t helper 1 cell differentiation through an epigenetic mechanism. Science. 2016;354:481\u20134.","journal-title":"Science"},{"key":"6009_CR39","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1038\/cr.2016.159","volume":"27","author":"J Liang","year":"2017","unstructured":"Liang J, Cao R, Wang X, Zhang Y, Wang P, Gao H, et al. Mitochondrial pkm2 regulates oxidative stress-induced apoptosis by stabilizing bcl2. Cell Res. 2017;27:329\u201351.","journal-title":"Cell Res"},{"key":"6009_CR40","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1038\/s41590-020-00829-6","volume":"22","author":"M Gu","year":"2021","unstructured":"Gu M, Zhou X, Sohn JH, Zhu L, Jie Z, Yang JY, et al. Nf-kappab-inducing kinase maintains t cell metabolic fitness in antitumor immunity. Nat Immunol. 2021;22:193\u2013204.","journal-title":"Nat Immunol"},{"key":"6009_CR41","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1038\/nature13490","volume":"513","author":"OR Colegio","year":"2014","unstructured":"Colegio OR, Chu NQ, Szabo AL, Chu T, Rhebergen AM, Jairam V, et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature. 2014;513:559\u201363.","journal-title":"Nature"},{"key":"6009_CR42","doi-asserted-by":"crossref","unstructured":"Yang L, Yan X, Chen J, Zhan Q, Hua Y, Xu S, et al. Hexokinase 2 discerns a novel circulating tumor cell population associated with poor prognosis in lung cancer patients. Proc Natl Acad Sci USA. 2021;118:e2012228118.","DOI":"10.1073\/pnas.2012228118"},{"key":"6009_CR43","doi-asserted-by":"publisher","first-page":"16284","DOI":"10.1021\/acs.analchem.0c04282","volume":"92","author":"Z Wang","year":"2020","unstructured":"Wang Z, Chen J, Yang L, Cao M, Yu Y, Zhang R, et al. Single-cell sequencing-enabled hexokinase 2 assay for noninvasive bladder cancer diagnosis and screening by detecting rare malignant cells in urine. Anal Chem. 2020;92:16284\u201392.","journal-title":"Anal Chem"},{"key":"6009_CR44","doi-asserted-by":"publisher","first-page":"1392","DOI":"10.1158\/0008-5472.CAN-17-2367","volume":"78","author":"R Rashmi","year":"2018","unstructured":"Rashmi R, Huang X, Floberg JM, Elhammali AE, Mccormick ML, Patti GJ, et al. Radioresistant cervical cancers are sensitive to inhibition of glycolysis and redox metabolism. Cancer Res. 2018;78:1392\u2013403.","journal-title":"Cancer Res"},{"key":"6009_CR45","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1016\/j.tips.2017.11.003","volume":"39","author":"H Wang","year":"2018","unstructured":"Wang H, Mu X, He H, Zhang X. Cancer radiosensitizers. Trends Pharmacol Sci. 2018;39:24\u201348.","journal-title":"Trends Pharmacol Sci"},{"key":"6009_CR46","doi-asserted-by":"publisher","first-page":"11206","DOI":"10.1073\/pnas.0800297105","volume":"105","author":"JM Han","year":"2008","unstructured":"Han JM, Park B, Park SG, Oh YS, Choi SJ, Lee SW, et al. Aimp2\/p38, the scaffold for the multi-trna synthetase complex, responds to genotoxic stresses via p53. Proc Natl Acad Sci USA. 2008;105:11206\u201311.","journal-title":"Proc Natl Acad Sci USA"},{"key":"6009_CR47","doi-asserted-by":"publisher","first-page":"3176","DOI":"10.1158\/1078-0432.CCR-17-3435","volume":"24","author":"F Wang","year":"2018","unstructured":"Wang F, Xia X, Yang C, Shen J, Mai J, Kim HC, et al. Smad4 gene mutation renders pancreatic cancer resistance to radiotherapy through promotion of autophagy. Clin Cancer Res. 2018;24:3176\u201385.","journal-title":"Clin Cancer Res"},{"key":"6009_CR48","doi-asserted-by":"publisher","first-page":"121287","DOI":"10.1016\/j.biomaterials.2021.121287","volume":"280","author":"Q Xu","year":"2022","unstructured":"Xu Q, Zhang H, Liu H, Han Y, Qiu W, Li Z. Inhibiting autophagy flux and dna repair of tumor cells to boost radiotherapy of orthotopic glioblastoma. Biomaterials. 2022;280:121287.","journal-title":"Biomaterials"},{"key":"6009_CR49","doi-asserted-by":"publisher","first-page":"963","DOI":"10.1080\/15548627.2015.1042195","volume":"11","author":"VP Tan","year":"2015","unstructured":"Tan VP, Miyamoto S. Hk2\/hexokinase-ii integrates glycolysis and autophagy to confer cellular protection. Autophagy. 2015;11:963\u20134.","journal-title":"Autophagy"},{"key":"6009_CR50","doi-asserted-by":"publisher","DOI":"10.1186\/1476-4598-12-152","volume":"12","author":"S Ganapathy-Kanniappan","year":"2013","unstructured":"Ganapathy-Kanniappan S, Geschwind JF. Tumor glycolysis as a target for cancer therapy: progress and prospects. Mol Cancer. 2013;12:152.","journal-title":"Mol Cancer"},{"key":"6009_CR51","doi-asserted-by":"publisher","first-page":"S21","DOI":"10.4103\/0973-1482.55136","volume":"5","author":"BS Dwarakanath","year":"2009","unstructured":"Dwarakanath BS, Singh D, Banerji AK, Sarin R, Venkataramana NK, Jalali R, et al. Clinical studies for improving radiotherapy with 2-deoxy-d-glucose: present status and future prospects. J Cancer Res Ther. 2009;5:S21\u20136.","journal-title":"J Cancer Res Ther"},{"key":"6009_CR52","doi-asserted-by":"publisher","first-page":"1749","DOI":"10.1158\/1078-0432.CCR-19-1515","volume":"26","author":"Y Tu","year":"2020","unstructured":"Tu Y, Chen Z, Zhao P, Sun G, Bao Z, Chao H, et al. Smoothened promotes glioblastoma radiation resistance via activating usp3-mediated claspin deubiquitination. Clin Cancer Res. 2020;26:1749\u201362.","journal-title":"Clin Cancer Res"}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41419-023-06009-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-023-06009-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-023-06009-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,1]],"date-time":"2023-08-01T04:02:32Z","timestamp":1690862552000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41419-023-06009-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,1]]},"references-count":52,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2023,8]]}},"alternative-id":["6009"],"URL":"https:\/\/doi.org\/10.1038\/s41419-023-06009-2","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,1]]},"assertion":[{"value":"30 January 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 July 2023","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 July 2023","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 August 2023","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"488"}}