{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T00:27:50Z","timestamp":1775694470703,"version":"3.50.1"},"reference-count":50,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2020,3,7]],"date-time":"2020-03-07T00:00:00Z","timestamp":1583539200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Qin Zhou","award":["grant numbers 81802549 and 81873932"],"award-info":[{"award-number":["grant numbers 81802549 and 81873932"]}]},{"name":"Yajun Xie","award":["grant numbers 31701218 and cstc2017jcyjA0390"],"award-info":[{"award-number":["grant numbers 31701218 and cstc2017jcyjA0390"]}]},{"name":"Qiying Yi","award":["grant number KJQN201900411"],"award-info":[{"award-number":["grant number KJQN201900411"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>High-dose dexamethasone (DEX) is used to treat chemotherapy-induced nausea and vomiting or to control immunotherapy-related autoimmune diseases in clinical practice. However, the underlying mechanisms of high-dose DEX in tumor progression remain unaddressed. Therefore, we explored the effects of high-dose DEX on tumor progression and the potential mechanisms of its anti-tumor function using immunohistochemistry, histological examination, real-time quantitative PCR (qPCR), and Western blotting. Tumor volume, blood vessel invasion, and levels of the cell proliferation markers Ki67 and c-Myc and the anti-apoptotic marker Bcl2 decreased in response to high-dose DEX. However, the cell apoptosis marker cleaved caspase 3 increased significantly in mice treated with 50 mg\/kg DEX compared with controls. Some genes associated with immune responses were significantly downregulated following treatment with 50 mg\/kg DEX e.g., Cxcl9, Cxcl10, Cd3e, Gzmb, Ifng, Foxp3, S100a9, Arg1, and Mrc1. In contrast, the M1-like tumor-associated macrophages (TAMs) activation marker Nos2 was shown to be increased. Moreover, the expression of peroxisome proliferator-activated receptors \u03b1 and \u03b3 (Ppar\u03b1 and Pparg, respectively) was shown to be significantly upregulated in livers or tumors treated with DEX. However, high-dose DEX treatment decreased the expression of glucose and lipid metabolic pathway-related genes such as glycolysis-associated genes (Glut1, Hk2, Pgk1, Idh3a), triglyceride (TG) synthesis genes (Gpam, Agpat2, Dgat1), exogenous free fatty acid (FFA) uptake-related genes (Fabp1, Slc27a4, and CD36), and fatty acid oxidation (FAO) genes (Acadm, Acaa1, Cpt1a, Pnpla2). In addition, increased serum glucose and decreased serum TG and non-esterified fatty acid (NEFA) were observed in DEX treated-xenografted tumor mice. These findings indicate that high-dose DEX-inhibited tumor progression is a complicated process, not only activated by M1-like TAMs, but also decreased by the uptake and consumption of glucose and lipids that block the raw material and energy supply of cancer cells. Activated M1-like TAMs and inefficient glucose and lipid metabolism delayed tumor cell growth and promoted apoptosis. These findings have important implications for the application of DEX combined with drugs that target key metabolism pathways for tumor therapy in clinical practice.<\/jats:p>","DOI":"10.3390\/ijms21051846","type":"journal-article","created":{"date-parts":[[2020,3,9]],"date-time":"2020-03-09T05:37:34Z","timestamp":1583732254000},"page":"1846","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["High-Dose Dexamethasone Manipulates the Tumor Microenvironment and Internal Metabolic Pathways in Anti-Tumor Progression"],"prefix":"10.3390","volume":"21","author":[{"given":"Lei","family":"Xu","sequence":"first","affiliation":[{"name":"The Ministry of Education Key Laboratory of Clinical Diagnostics, School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hua","family":"Xia","sequence":"additional","affiliation":[{"name":"The Ministry of Education Key Laboratory of Clinical Diagnostics, School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dongsheng","family":"Ni","sequence":"additional","affiliation":[{"name":"The Ministry of Education Key Laboratory of Clinical Diagnostics, School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanxia","family":"Hu","sequence":"additional","affiliation":[{"name":"The Ministry of Education Key Laboratory of Clinical Diagnostics, School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianing","family":"Liu","sequence":"additional","affiliation":[{"name":"The Ministry of Education Key Laboratory of Clinical Diagnostics, School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yao","family":"Qin","sequence":"additional","affiliation":[{"name":"The Ministry of Education Key Laboratory of Clinical Diagnostics, School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qin","family":"Zhou","sequence":"additional","affiliation":[{"name":"The Ministry of Education Key Laboratory of Clinical Diagnostics, School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiying","family":"Yi","sequence":"additional","affiliation":[{"name":"Laboratory Animal Center, Chongqing Medical University, Chongqing 400016, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yajun","family":"Xie","sequence":"additional","affiliation":[{"name":"The Ministry of Education Key Laboratory of Clinical Diagnostics, School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,3,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.critrevonc.2018.03.015","article-title":"Glucocorticoids as an adjunct to oncologic treatment in solid malignancies\u2014Not an innocent bystander","volume":"126","author":"Perets","year":"2018","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.ejphar.2013.10.008","article-title":"The cellular mechanisms of the antiemetic action of dexamethasone and related glucocorticoids against vomiting","volume":"722","author":"Chu","year":"2014","journal-title":"Eur. J. Pharmacol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3003","DOI":"10.1158\/1078-0432.CCR-05-2085","article-title":"Glucocorticoids suppress tumor angiogenesis and in vivo growth of prostate cancer cells","volume":"12","author":"Yano","year":"2006","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Lin, K., Sun, S., Wu, J., and Wang, L. (2017). Low-dose glucocorticoids suppresses ovarian tumor growth and metastasis in an immunocompetent syngeneic mouse model. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0178937"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1038\/s41419-018-0558-1","article-title":"A dual role for glucocorticoid-induced leucine zipper in glucocorticoid function: Tumor growth promotion or suppression?","volume":"9","author":"Ayroldi","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"(1998). Double-blind, dose-finding study of four intravenous doses of dexamethasone in the prevention of cisplatin-induced acute emesis. Italian Group for Antiemetic Research. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol., 16, 2937\u20132942.","DOI":"10.1200\/JCO.1998.16.9.2937"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e11042","DOI":"10.1097\/MD.0000000000011042","article-title":"A phase 2 study of fosaprepitant combined with high-dose dexamethasone for Japanese cancer patients receiving highly emetogenic chemotherapy","volume":"97","author":"Kumagai","year":"2018","journal-title":"Medicine"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1186\/s40425-018-0371-5","article-title":"Dexamethasone-induced immunosuppression: Mechanisms and implications for immunotherapy","volume":"6","author":"Giles","year":"2018","journal-title":"J. Immunother. Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"521","DOI":"10.18632\/aging.100797","article-title":"Corticosteroids and immune checkpoint blockade","volume":"7","author":"Min","year":"2015","journal-title":"Aging"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1126\/science.aaa8172","article-title":"The future of immune checkpoint therapy","volume":"348","author":"Sharma","year":"2015","journal-title":"Science"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1016\/j.cmet.2016.10.010","article-title":"Tumor-Induced IL-6 Reprograms Host Metabolism to Suppress Anti-tumor Immunity","volume":"24","author":"Flint","year":"2016","journal-title":"Cell Metab."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.2147\/CMAR.S187659","article-title":"Dexamethasone inhibits the proliferation of tumor cells","volume":"11","author":"Wu","year":"2019","journal-title":"Cancer Manag. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.gene.2019.01.047","article-title":"Long-term and high dose dexamethasone injection decreases the expression of Immunoglobulin Heavy (Light) Chain Variable Region Genes (IGH(L)Vs) in the mouse spleen","volume":"695","author":"Qi","year":"2019","journal-title":"Gene"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e31","DOI":"10.1038\/bcj.2011.27","article-title":"Glucocorticoid-induced cell death is mediated through reduced glucose metabolism in lymphoid leukemia cells","volume":"1","author":"Buentke","year":"2011","journal-title":"Blood Cancer J."},{"key":"ref_15","first-page":"G1141","article-title":"Glucocorticoids inhibit mitochondrial matrix acyl-CoA dehydrogenases and fatty acid beta-oxidation","volume":"272","author":"Robin","year":"1997","journal-title":"Am. J. Physiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/S0005-2760(97)00213-0","article-title":"Indirect dexamethasone down-regulation of the liver fatty acid-binding protein expression in rat liver","volume":"1391","author":"Foucaud","year":"1998","journal-title":"Biochim. Et Biophys. Acta"},{"key":"ref_17","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_18","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.ejphar.2014.09.013","article-title":"Ciglitazone enhances ovarian cancer cell death via inhibition of glucose transporter-1","volume":"743","author":"Shin","year":"2014","journal-title":"Eur. J. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"8631","DOI":"10.1021\/acs.jmedchem.7b01231","article-title":"Methyl 3-(3-(4-(2,4,4-Trimethylpentan-2-yl)phenoxy)-propanamido)benzoate as a Novel and Dual Malate Dehydrogenase (MDH) 1\/2 Inhibitor Targeting Cancer Metabolism","volume":"60","author":"Naik","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1038\/nrc.2016.89","article-title":"The multifaceted roles of fatty acid synthesis in cancer","volume":"16","author":"Schulze","year":"2016","journal-title":"Nat. Rev. Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1498","DOI":"10.1038\/nm.2492","article-title":"Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth","volume":"17","author":"Nieman","year":"2011","journal-title":"Nat. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e189","DOI":"10.1038\/oncsis.2015.49","article-title":"Lipid metabolic reprogramming in cancer cells","volume":"5","author":"Vasseur","year":"2016","journal-title":"Oncogenesis"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/s12964-019-0342-6","article-title":"Plasmodium infection inhibits the expansion and activation of MDSCs and Tregs in the tumor microenvironment in a murine Lewis lung cancer model","volume":"17","author":"Adah","year":"2019","journal-title":"Cell Commun. Signal. Ccs"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2243","DOI":"10.3389\/fimmu.2019.02243","article-title":"S100A9 Regulates MDSCs-Mediated Immune Suppression via the RAGE and TLR4 Signaling Pathways in Colorectal Carcinoma","volume":"10","author":"Huang","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1111\/nep.13635","article-title":"Protease-activated receptor 2 does not contribute to renal inflammation or fibrosis in the obstructed kidney","volume":"24","author":"Ma","year":"2019","journal-title":"Nephrology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"441","DOI":"10.3389\/fphar.2019.00441","article-title":"Proteomic Analysis Provides Insights Into the Therapeutic Effect of GU-BEN-FANG-XIAO Decoction on a Persistent Asthmatic Mouse Model","volume":"10","author":"Liu","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1038\/ncb3124","article-title":"Metabolic pathways promoting cancer cell survival and growth","volume":"17","author":"Boroughs","year":"2015","journal-title":"Nat. Cell Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1038\/s41557-018-0132-6","article-title":"Chromopynones are pseudo natural product glucose uptake inhibitors targeting glucose transporters GLUT-1 and -3","volume":"10","author":"Karageorgis","year":"2018","journal-title":"Nat. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1038\/s41419-019-1549-6","article-title":"B7-H3 promotes aerobic glycolysis and chemoresistance in colorectal cancer cells by regulating HK2","volume":"10","author":"Shi","year":"2019","journal-title":"Cell Death Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1016\/j.ccr.2012.08.014","article-title":"Metabolic signatures uncover distinct targets in molecular subsets of diffuse large B cell lymphoma","volume":"22","author":"Caro","year":"2012","journal-title":"Cancer Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1200\/JCO.2007.13.9717","article-title":"Anti-apoptosis mechanisms in malignant gliomas","volume":"26","author":"Ziegler","year":"2008","journal-title":"J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"8972570","DOI":"10.1155\/2016\/8972570","article-title":"\u03b3PPAR as a Novel Therapeutic Target in Lung Cancer","volume":"2016","author":"Reddy","year":"2016","journal-title":"Ppar Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1638","DOI":"10.1248\/bpb.b18-00132","article-title":"Ginsenoside Rg1 Protects against Non-alcoholic Fatty Liver Disease by Ameliorating Lipid Peroxidation, Endoplasmic Reticulum Stress, and Inflammasome Activation","volume":"41","author":"Xu","year":"2018","journal-title":"Biol. Pharm. Bull."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Li, T., Hu, S., Pang, X., Wang, J., Yin, J., Li, F., Wang, J., Yang, X., Xia, B., and Liu, Y. (2020). The marine-derived furanone reduces intracellular lipid accumulation in vitro by targeting LXR\u03b1 and PPAR\u03b1. J. Cell. Mol. Med.","DOI":"10.1111\/jcmm.15012"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1038\/sj.leu.2405039","article-title":"The BCL2 rheostat in glucocorticoid-induced apoptosis of acute lymphoblastic leukemia","volume":"22","author":"Ploner","year":"2008","journal-title":"Leukemia"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1038\/nri.2017.1","article-title":"Immune regulation by glucocorticoids","volume":"17","author":"Cain","year":"2017","journal-title":"Nat. Rev. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.canlet.2015.07.039","article-title":"Tumor microenvironment: Sanctuary of the devil","volume":"368","author":"Hui","year":"2015","journal-title":"Cancer Lett."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1007\/s00262-018-2175-3","article-title":"Targeting myeloid-derived suppressor cells for cancer immunotherapy","volume":"67","author":"Liu","year":"2018","journal-title":"Cancer Immunol. Immunother. CII"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.freeradbiomed.2019.12.018","article-title":"Scavenging reactive oxygen species selectively inhibits M2 macrophage polarization and their pro-tumorigenic function in part, via Stat3 suppression","volume":"147","author":"Griess","year":"2020","journal-title":"Free Radic. Biol. Med."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Chen, Z., Zhuo, R., Zhao, Y., Yang, L., Zhou, Y., Cheng, X., Peng, L., Jin, X., and Wang, Y. (2020). Oleoylethanolamide stabilizes atherosclerotic plaque through regulating macrophage polarization via AMPK-PPAR\u03b1 pathway. Biochem. Biophys. Res. Commun.","DOI":"10.1016\/j.bbrc.2020.01.103"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.yexcr.2018.04.023","article-title":"ER-localized protein-Herpud1 is a new mediator of IL-4-induced macrophage polarization and migration","volume":"368","author":"Li","year":"2018","journal-title":"Exp. Cell Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e1808303","DOI":"10.1002\/adma.201808303","article-title":"Tailoring Nanomaterials for Targeting Tumor-Associated Macrophages","volume":"31","author":"Ovais","year":"2019","journal-title":"Adv. Mater."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"161","DOI":"10.3109\/1061186X.2012.736998","article-title":"Glycolytic enzymes PGK1 and PKM2 as novel transcriptional targets of PPAR\u03b3 in breast cancer pathophysiology","volume":"21","author":"Shashni","year":"2013","journal-title":"J. Drug Target."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4589","DOI":"10.1158\/0008-5472.CAN-16-2065","article-title":"Glycerol-3-phosphate Acyltransferase 1 Promotes Tumor Cell Migration and Poor Survival in Ovarian Carcinoma","volume":"77","author":"Marchan","year":"2017","journal-title":"Cancer Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.ygcen.2017.11.011","article-title":"Chronic dexamethasone exposure markedly decreased the hepatic triglyceride accumulation in growing goats","volume":"259","author":"Chen","year":"2018","journal-title":"Gen. Comp. Endocrinol."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Yen, M., Chou, S., Kan, J., Kuo, P., Hou, M., and Hsu, Y. (2018). Solute Carrier Family 27 Member 4 (SLC27A4) Enhances Cell Growth, Migration, and Invasion in Breast Cancer Cells. Int. J. Mol. Sci.","DOI":"10.3390\/ijms19113434"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"443","DOI":"10.3109\/10253890.2011.639413","article-title":"Dexamethasone facilitates lipid accumulation in chicken skeletal muscle","volume":"15","author":"Wang","year":"2012","journal-title":"Stress"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.jsbmb.2018.10.013","article-title":"MicroRNA-128 is involved in dexamethasone-induced lipid accumulation via repressing SIRT1 expression in cultured pig preadipocytes","volume":"186","author":"Pan","year":"2019","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"875","DOI":"10.3892\/or.2014.3655","article-title":"Lactate promotes resistance to glucose starvation via upregulation of Bcl-2 mediated by mTOR activation","volume":"33","author":"Huang","year":"2015","journal-title":"Oncol. Rep."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1835","DOI":"10.1016\/j.biopha.2018.10.028","article-title":"Anti-proliferative activity of Origanum vulgare inhibited lipogenesis and induced mitochondrial mediated apoptosis in human stomach cancer cell lines","volume":"108","author":"Balusamy","year":"2018","journal-title":"Biomed. Pharmacother."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/5\/1846\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:05:04Z","timestamp":1760173504000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/5\/1846"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,7]]},"references-count":50,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2020,3]]}},"alternative-id":["ijms21051846"],"URL":"https:\/\/doi.org\/10.3390\/ijms21051846","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,7]]}}}