{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T11:19:46Z","timestamp":1781781586687,"version":"3.54.5"},"reference-count":41,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2020,1,13]],"date-time":"2020-01-13T00:00:00Z","timestamp":1578873600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Grant-in-Aid for Scientific Research (KAKENHI) from the Japan Society for the Promotion of Science","award":["25462071, 16K10555, and 19K09229"],"award-info":[{"award-number":["25462071, 16K10555, and 19K09229"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Hypoxic cellular proliferation is a common feature of tumor cells and is associated with tumor progression. Therefore, the inhibition of hypoxic cellular proliferation is expected to regulate malignancy processes. Licochalcone A (LicA) is known to show inhibitory effects on cell growth in normoxia, but it is unclear whether LicA exerts similar effects in hypoxia. Here, we studied the inhibitory activity of LicA in the hypoxic cellular proliferation of tumor cells and its molecular mechanism using human cell lines derived from various tumors including neuroblastoma and colorectal cancer. LicA inhibited cell growth at a 50% inhibitory concentration between 7.0 and 31.1 \u00b5M in hypoxia. LicA significantly suppressed hypoxic induction of tropomyosin receptor kinase B (TrkB) gene expression at the transcription level. LicA also downregulated mRNA levels of the TrkB high-affinity ligand brain-derived neurotrophic factor, but not neurotrophin-4, another TrkB ligand, or glyceraldehyde-3-phosphate dehydrogenase, indicating that the inhibitory activity of LicA is selective. Since both LicA-treatment and TrkB-knockdown decreased activation of protein kinase B in hypoxia, LicA exerts its inhibitory effect against hypoxic cell growth through inhibition of the TrkB-AKT axis. These results suggest that LicA has therapeutic potential for malignant tumors including neuroblastoma and colorectal cancer.<\/jats:p>","DOI":"10.3390\/ijms21020506","type":"journal-article","created":{"date-parts":[[2020,1,15]],"date-time":"2020-01-15T03:20:22Z","timestamp":1579058422000},"page":"506","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Licochalcone A Inhibits BDNF and TrkB Gene Expression and Hypoxic Growth of Human Tumor Cell Lines"],"prefix":"10.3390","volume":"21","author":[{"given":"Michitsune","family":"Arita","sequence":"first","affiliation":[{"name":"Department of Molecular Immunology, Toho University School of Medicine, Tokyo 143-8540, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junichi","family":"Koike","sequence":"additional","affiliation":[{"name":"Department of Surgery, Toho University School of Medicine, Tokyo 143-8540, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuji","family":"Yoshikawa","sequence":"additional","affiliation":[{"name":"Cokey Systems, Co., Ltd., Tokyo 102-0075, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1565-8804","authenticated-orcid":false,"given":"Motonari","family":"Kondo","sequence":"additional","affiliation":[{"name":"Department of Molecular Immunology, Toho University School of Medicine, Tokyo 143-8540, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiromichi","family":"Hemmi","sequence":"additional","affiliation":[{"name":"Department of Molecular Immunology, Toho University School of Medicine, Tokyo 143-8540, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,1,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1186\/1476-4598-12-152","article-title":"Tumor glycolysis as a target for cancer therapy: Progress and prospects","volume":"12","author":"Geschwind","year":"2013","journal-title":"Mol. Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.pharmthera.2016.04.009","article-title":"Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer","volume":"164","author":"Wigerup","year":"2016","journal-title":"Pharmacol. Ther."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1038\/nrc.2017.77","article-title":"Tumour acidosis: From the passenger to the driver\u2019s seat","volume":"17","author":"Corbet","year":"2017","journal-title":"Nat. Rev. Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1007\/s10585-018-9906-x","article-title":"The Kraken Wakes: Induced EMT as a driver of tumour aggression and poor outcome","volume":"35","author":"Redfern","year":"2018","journal-title":"Clin. Exp. Metastasis"},{"key":"ref_5","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_6","doi-asserted-by":"crossref","first-page":"38908","DOI":"10.18632\/oncotarget.7676","article-title":"The sweet trap in tumors: Aerobic glycolysis and potential targets for therapy","volume":"7","author":"Yu","year":"2016","journal-title":"Oncotarget"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"490","DOI":"10.3748\/wjg.v22.i2.490","article-title":"Tropomyosin-related kinase B\/brain derived-neurotrophic factor signaling pathway as a potential therapeutic target for colorectal cancer","volume":"22","author":"Akil","year":"2016","journal-title":"World J. Gastroenterol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3481","DOI":"10.1016\/j.bbamcr.2013.06.026","article-title":"Anoikis molecular pathways and its role in cancer progression","volume":"1833","author":"Paoli","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/S0304-3835(00)00715-1","article-title":"Human neuroblastomas with unfavorable biologies express high levels of brain-derived neurotrophic factor mRNA and a variety of its variants","volume":"164","author":"Aoyama","year":"2001","journal-title":"Cancer Lett."},{"key":"ref_10","first-page":"759","article-title":"Expression and function of TRK-B and BDNF in human neuroblastomas","volume":"14","author":"Nakagawara","year":"1994","journal-title":"Mol. Cell Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4249","DOI":"10.1158\/0008-5472.CAN-05-2789","article-title":"Brain-derived neurotrophic factor activation of TrkB induces vascular endothelial growth factor expression via hypoxia-inducible factor-1alpha in neuroblastoma cells","volume":"66","author":"Nakamura","year":"2006","journal-title":"Cancer Res."},{"key":"ref_12","first-page":"3983","article-title":"BDNF: An Oncogene or Tumor Suppressor?","volume":"37","author":"Radin","year":"2017","journal-title":"Anticancer Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5962","DOI":"10.1158\/1078-0432.CCR-08-0651","article-title":"On Trk\u2014The TrkB Signal Transduction Pathway Is an Increasingly Important Target in Cancer Biology","volume":"15","author":"Thiele","year":"2009","journal-title":"Clin. Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1034","DOI":"10.1038\/nature02765","article-title":"Suppression of anoikis and induction of metastasis by the neurotrophic receptor TrkB","volume":"430","author":"Douma","year":"2004","journal-title":"Nature"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3722","DOI":"10.1128\/MCB.01164-08","article-title":"A Twist-Snail axis critical for TrkB-induced epithelial-mesenchymal transition-like transformation, anoikis resistance, and metastasis","volume":"29","author":"Smit","year":"2009","journal-title":"Mol. Cell Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"10299","DOI":"10.1073\/pnas.1404399111","article-title":"Neurotrophin receptor TrkB promotes lung adenocarcinoma metastasis","volume":"111","author":"Sinkevicius","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"14379","DOI":"10.1074\/jbc.M609857200","article-title":"Hypoxia-inducible factor-1 (HIF-1) is a transcriptional activator of the TrkB neurotrophin receptor gene","volume":"282","author":"Martens","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"28851","DOI":"10.18632\/oncotarget.4767","article-title":"Licochalcone A induces autophagy through PI3K\/Akt\/mTOR inactivation and autophagy suppression enhances Licochalcone A-induced apoptosis of human cervical cancer cells","volume":"6","author":"Tsai","year":"2015","journal-title":"Oncotarget"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"12139","DOI":"10.1007\/s13277-014-2519-3","article-title":"Licochalcone A inhibits the migration and invasion of human lung cancer cells via inactivation of the Akt signaling pathway with downregulation of MMP-1\/-3 expression","volume":"35","author":"Huang","year":"2014","journal-title":"Tumour Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"10336","DOI":"10.1038\/srep10336","article-title":"Licochalcone A-induced human gastric cancer BGC-823 cells apoptosis by regulating ROS-mediated MAPKs and PI3K\/AKT signaling pathways","volume":"5","author":"Hao","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_21","first-page":"1181","article-title":"Licochalcone A suppresses hexokinase 2-mediated tumor glycolysis in gastric cancer via downregulation of the Akt signaling pathway","volume":"39","author":"Wu","year":"2018","journal-title":"Oncol. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s13277-016-5433-z","article-title":"PI3K and MAPK pathways mediate the BDNF\/TrkB-increased metastasis in neuroblastoma","volume":"37","author":"Hua","year":"2016","journal-title":"Tumour Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"563","DOI":"10.2174\/1871520611313040005","article-title":"Cell survival signaling in neuroblastoma","volume":"13","author":"Megison","year":"2013","journal-title":"Anticancer Agents Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1007\/s00018-005-5490-8","article-title":"The neurotrophic receptor TrkB: A drug target in anti-cancer therapy?","volume":"63","author":"Desmet","year":"2006","journal-title":"Cell Mol. Life Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1586\/era.11.150","article-title":"BDNF\/TrkB signaling as an anti-tumor target","volume":"11","author":"Roesler","year":"2011","journal-title":"Expert Rev. Anticancer Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"D260","DOI":"10.1093\/nar\/gkx1126","article-title":"JASPAR 2018: Update of the open-access database of transcription factor binding profiles and its web framework","volume":"46","author":"Khan","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_27","first-page":"2031","article-title":"Targeting the BDNF\/TrkB pathway for the treatment of tumors","volume":"17","author":"Meng","year":"2019","journal-title":"Oncol. Lett."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/0014-5793(89)80790-2","article-title":"Characterization of DNA rearrangements of N-myc gene amplification in three neuroblastoma cell lines by pulsed-field gel electrophoresis","volume":"250","author":"Kato","year":"1989","journal-title":"FEBS Lett."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1038\/onc.2009.512","article-title":"Myc proteins as therapeutic targets","volume":"29","author":"Gustafson","year":"2010","journal-title":"Oncogene"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e71","DOI":"10.1038\/oncsis.2013.35","article-title":"Epigenetic and genetic features of 24 colon cancer cell lines","volume":"2","author":"Ahmed","year":"2013","journal-title":"Oncogenesis"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1111\/j.1600-0463.2009.02577.x","article-title":"Overexpression of TrkB promotes the progression of colon cancer","volume":"118","author":"Yu","year":"2010","journal-title":"APMIS"},{"key":"ref_32","first-page":"1364","article-title":"Morphology, growth, chromosomal pattern and fibrinolytic activity of two new human neuroblastoma cell lines","volume":"37","author":"Seeger","year":"1977","journal-title":"Cancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1007\/s00280-002-0452-4","article-title":"Establishment of cisplatin-resistant variants of human neuroblastoma cell lines, TGW and GOTO, and their drug cross-resistance profiles","volume":"49","author":"Iwasaki","year":"2002","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1016\/j.bbamcr.2012.01.017","article-title":"Down-regulation of MutS homolog 3 by hypoxia in human colorectal cancer","volume":"1823","author":"Li","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"28896","DOI":"10.1074\/jbc.M400126200","article-title":"N-myc regulates parkin expression","volume":"279","author":"West","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1016\/j.jvs.2003.10.049","article-title":"Temporal genomics of vein bypass grafting through oligonucleotide microarray analysis","volume":"39","author":"Kalish","year":"2004","journal-title":"J. Vasc. Surg."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1620\/tjem.201.229","article-title":"A novel dysfunctional p53 mutation in the human neuroblastoma cell line TGW","volume":"201","author":"Sugiyama","year":"2003","journal-title":"Tohoku J. Exp. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/S0378-1119(03)00385-8","article-title":"Multiple sites required for expression in 5\u2019-flanking region of the hMLH1 gene","volume":"306","author":"Arita","year":"2003","journal-title":"Gene"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1006\/abio.1993.1313","article-title":"A semidry electroblotting system efficiently transfers both high- and low-molecular-weight proteins separated by SDS-PAGE","volume":"212","year":"1993","journal-title":"Anal. Biochem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1006\/bbrc.2001.6301","article-title":"Analysis of the Human TrkB Gene Genomic Organization Reveals Novel TrkB Isoforms, Unusual Gene Length, and Splicing Mechanism","volume":"290","author":"Stoilov","year":"2002","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1111\/j.1471-4159.2007.04851.x","article-title":"Robust stimulation of TrkB induces delayed increases in BDNF and Arc mRNA expressions in cultured rat cortical neurons via distinct mechanisms","volume":"103","author":"Yasuda","year":"2007","journal-title":"J. Neurochem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/2\/506\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T13:19:40Z","timestamp":1760361580000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/2\/506"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,13]]},"references-count":41,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2020,1]]}},"alternative-id":["ijms21020506"],"URL":"https:\/\/doi.org\/10.3390\/ijms21020506","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,1,13]]}}}