{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T17:10:10Z","timestamp":1781716210800,"version":"3.54.5"},"reference-count":43,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2018,5,8]],"date-time":"2018-05-08T00:00:00Z","timestamp":1525737600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Taiwan Ministry of Science and Technology","award":["(MOST-105-2320-B-182-020-MY3"],"award-info":[{"award-number":["(MOST-105-2320-B-182-020-MY3"]}]},{"DOI":"10.13039\/100012553","name":"Chang Gung Memorial Hospital","doi-asserted-by":"publisher","award":["CRRPG2D0013, CRRPD1F0041-2, CMRPD1F0141-3"],"award-info":[{"award-number":["CRRPG2D0013, CRRPD1F0041-2, CMRPD1F0141-3"]}],"id":[{"id":"10.13039\/100012553","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Caffeic acid phenethyl ester (CAPE), a bioactive component extracted from propolis, is widely studied due to its anti-cancer effect. Nasopharyngeal carcinoma (NPC) is distinct from other head and neck carcinomas and has a high risk of distant metastases. N-myc downstream regulated gene 1 (NDRG1) is demonstrated as a tumor suppressor gene in several cancers. Our result showed that CAPE treatment could repress NPC cell growth, through induction of S phase cell cycle arrest, and invasion. CAPE treatment stimulated NDRG1 expression in NPC cells. NDRG1 knockdown increased NPC cell proliferation and invasion and rendered NPC cells less responsive to CAPE growth-inhibiting effect, indicating CAPE repressed NPC cell growth partly through NDRG1indcution. CAPE treatment increased phosphorylation of ERK, JNK, and p38 in a dose- and time-dependent manner. Pre-treatments by inhibitors of ERK (PD0325901), JNK (SP600125), or p38 (SB201290), respectively, all could partly inhibit the CAPE effect on NDRG1 induction in NPC cells. Further, STAT3 activity was also repressed by CAPE in NPC cells. In summary, CAPE attenuates NPC cell proliferation and invasion by upregulating NDRG1 expression via MAPK pathway and by inhibiting phosphorylation of STAT3. Considering the poor prognosis of NPC patients with metastasis, CAPE could be a promising agent against NPC.<\/jats:p>","DOI":"10.3390\/ijms19051397","type":"journal-article","created":{"date-parts":[[2018,5,8]],"date-time":"2018-05-08T02:48:08Z","timestamp":1525747688000},"page":"1397","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Caffeic Acid Phenethyl Ester Induces N-myc Downstream Regulated Gene 1 to Inhibit Cell Proliferation and Invasion of Human Nasopharyngeal Cancer Cells"],"prefix":"10.3390","volume":"19","author":[{"given":"Kun-Chun","family":"Chiang","sequence":"first","affiliation":[{"name":"Zebrafish Center, Department of General Surgery, Chang Gung Memorial Hospital, Keelung 204, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0979-7912","authenticated-orcid":false,"given":"Shih-Wei","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai-Ping","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsui-Hsia","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kang-Shuo","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke-Hung","family":"Tsui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Syuan","family":"Shin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiu-Chun","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Chao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8524-8253","authenticated-orcid":false,"given":"Horng-Heng","family":"Juang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,5,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1158\/1055-9965.EPI-15-0578","article-title":"Global cancer incidence and mortality rates and trends\u2014An Update","volume":"25","author":"Torre","year":"2016","journal-title":"Cancer Epidemiol. Prev. Biomark."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.clon.2012.10.006","article-title":"Nasopharyngeal carcinoma: A retrospective review of demographics, treatment and patient outcome in a single centre","volume":"25","author":"Colaco","year":"2013","journal-title":"Clin. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"E359","DOI":"10.1002\/ijc.29210","article-title":"Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012","volume":"136","author":"Ferlay","year":"2015","journal-title":"Int. J. Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1016\/S0140-6736(15)00055-0","article-title":"Nasopharyngeal carcinoma","volume":"387","author":"Chua","year":"2016","journal-title":"Lancet"},{"key":"ref_5","first-page":"2064","article-title":"The anticancer mechanism of caffeic acid phenethyl ester (CAPE): Review of melanomas, lung and prostate cancers","volume":"16","author":"Ozturk","year":"2012","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2581","DOI":"10.1111\/febs.12242","article-title":"Caffeic acid phenethyl ester induces E2F-1-mediated growth inhibition and cell-cycle arrest in human cervical cancer cells","volume":"280","author":"Hsu","year":"2013","journal-title":"FEBS J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"10748","DOI":"10.3390\/ijms160510748","article-title":"Caffeic acid phenethyl ester is a potential therapeutic agent for oral cancer","volume":"16","author":"Kuo","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"7907","DOI":"10.1021\/jf034729d","article-title":"Inhibitory effect of caffeic acid phenethyl ester on angiogenesis, tumor invasion, and metastasis","volume":"51","author":"Liao","year":"2003","journal-title":"J. Agric. Food Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1252","DOI":"10.1016\/j.ijrobp.2005.08.001","article-title":"Caffeic acid phenethyl ester preferentially sensitizes CT26 colorectal adenocarcinoma to ionizing radiation without affecting bone marrow radioresponse","volume":"63","author":"Chen","year":"2005","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1007\/s10637-011-9667-8","article-title":"Caffeic acid phenethyl ester (CAPE) derived from propolis, a honeybee product, inhibits growth of breast cancer stem cells","volume":"30","author":"Omene","year":"2012","journal-title":"Investig. New Drugs"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.canlet.2011.04.012","article-title":"Caffeic acid phenethyl ester (CAPE), derived from a honeybee product propolis, exhibits a diversity of anti-tumor effects in pre-clinical models of human breast cancer","volume":"308","author":"Wu","year":"2011","journal-title":"Cancer Lett."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1158\/1940-6207.CAPR-12-0004-T","article-title":"Caffeic acid phenethyl ester suppresses the proliferation of human prostate cancer cells through inhibition of p70S6K and Akt signaling networks","volume":"5","author":"Chuu","year":"2012","journal-title":"Cancer Prev. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1269\/jrr.45.253","article-title":"Cell killing and radiosensitization by caffeic acid phenethyl ester (CAPE) in lung cancer cells","volume":"45","author":"Chen","year":"2004","journal-title":"J. Radiat. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1600842","DOI":"10.1002\/mnfr.201600842","article-title":"Caffeic acid phenethyl ester upregulates N-myc downstream regulated gene 1 via ERK pathway to inhibit human oral cancer cell growth in vitro and in vivo","volume":"61","author":"Chung","year":"2017","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"6793456","DOI":"10.1155\/2017\/6793456","article-title":"Induction of cell cycle arrest and apoptotic response of head and neck squamous carcinoma cells (Detroit 562) by caffeic acid and caffeic acid phenethyl ester derivative","volume":"2017","author":"Dziedzic","year":"2017","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.canlet.2014.08.035","article-title":"N-myc downstream-regulated gene 1 downregulates cell proliferation, invasiveness, and tumorigenesis in human oral squamous cell carcinoma","volume":"355","author":"Lee","year":"2014","journal-title":"Cancer Lett."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"10157","DOI":"10.1007\/s11033-012-1889-0","article-title":"Prognostic significance of NDRG1 expression in oral and oropharyngeal squamous cell carcinoma","volume":"39","author":"Nunes","year":"2012","journal-title":"Mol. Biol. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1292","DOI":"10.1111\/j.1349-7006.2010.01529.x","article-title":"Expression of NDRG2 in esophageal squamous cell carcinoma","volume":"101","author":"Shi","year":"2010","journal-title":"Cancer Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1785","DOI":"10.1016\/j.bbrc.2009.12.156","article-title":"NDRG2 is a candidate tumor-suppressor for oral squamous-cell carcinoma","volume":"391","author":"Furuta","year":"2010","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1876","DOI":"10.1016\/j.bbadis.2015.06.009","article-title":"NDRG1 attenuates epithelial-mesenchymal transition of nasopharyngeal cancer cells via blocking Smad2 signaling","volume":"1852","author":"Hu","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Kang, M., Lee, K.H., Lee, H.S., Jeong, C.W., Ku, J.H., Kim, H.H., and Kwak, C. (2017). Concurrent treatment with simvastatin and NF-\u03baB inhibitor in human castration-resistant prostate cancer cells exerts synergistic anti-cancer effects via control of the NF-\u03baB\/LIN28\/let-7 miRNA signaling pathway. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0184644"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Kaba\u0142a-Dzik, A., Rzepecka-Stojko, A., Kubina, R., Jastrz\u0119bska-Stojko, \u017b., Stojko, R., Wojtyczka, R.D., and Stojko, J. (2017). Migration rate inhibition of breast cancer cells treated by caffeic acid and caffeic acid phenethyl ester: An in vitro comparison study. Nutrients, 9.","DOI":"10.3390\/nu9101144"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Ishida, Y., Gao, R., Shah, N., Bhargava, P., Furune, T., Kaul, S.C., Terao, K., and Wadhwa, R. (2018). Anticancer Activity in Honeybee Propolis: Functional Insights to the Role of Caffeic Acid Phenethyl Ester and Its Complex with \u03b3-Cyclodextrin. Integr. Cancer Ther.","DOI":"10.1177\/1534735417753545"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1038\/nrc2602","article-title":"Cell cycle, CDKs and cancer: A changing paradigm","volume":"9","author":"Malumbres","year":"2009","journal-title":"Nat. Rev. Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"130083","DOI":"10.1098\/rsob.130083","article-title":"Coordinating cell polarity and cell cycle progression: What can we learn from flies and worms?","volume":"3","author":"Noatynska","year":"2013","journal-title":"Open Biol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Lin, H.P., Jiang, S.S., and Chuu, C.P. (2012). Caffeic acid phenethyl ester causes p21 induction, Akt signaling reduction, and growth inhibition in PC-3 human prostate cancer cells. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0031286"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1050","DOI":"10.3892\/mmr.2015.3492","article-title":"Overexpression of N myc downstream regulated gene 1 inhibits human glioma proliferation and invasion via phosphoinositide 3 kinase\/AKT pathways","volume":"12","author":"Ma","year":"2015","journal-title":"Mol. Med. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2355","DOI":"10.1093\/carcin\/bgl146","article-title":"The metastasis suppressor, Ndrg-1: A new ally in the fight against cancer","volume":"27","author":"Kovacevic","year":"2006","journal-title":"Carcinogenesis"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3296","DOI":"10.1158\/1078-0432.CCR-04-2417","article-title":"Drg1 expression in 131 colorectal liver metastases: Correlation with clinical variables and patient outcomes","volume":"11","author":"Shah","year":"2005","journal-title":"Clin. Cancer Res."},{"key":"ref_30","first-page":"3950","article-title":"Drg1, a novel target for modulating sensitivity to CPT-11 in colon cancer cells","volume":"62","author":"Motwani","year":"2002","journal-title":"Cancer Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2684","DOI":"10.1128\/JVI.03189-14","article-title":"Clustered microRNAs of the Epstein-Barr virus cooperatively downregulate an epithelial cell-specific metastasis suppressor","volume":"89","author":"Kanda","year":"2015","journal-title":"J. Virol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1038\/nrm1835","article-title":"Complex networks orchestrate epithelial-mesenchymal transitions","volume":"7","author":"Thiery","year":"2006","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"8319","DOI":"10.1158\/0008-5472.CAN-06-0410","article-title":"Reassessing epithelial to mesenchymal transition as a prerequisite for carcinoma invasion and metastasis","volume":"66","author":"Christiansen","year":"2006","journal-title":"Cancer Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1038\/nrc2131","article-title":"Snail, Zeb and bHLH factors in tumour progression: An alliance against the epithelial phenotype?","volume":"7","author":"Peinado","year":"2007","journal-title":"Nat. Rev. Cancer"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"6684","DOI":"10.18632\/oncotarget.3246","article-title":"Caffeic acid phenethyl ester induced cell cycle arrest and growth inhibition in androgen-independent prostate cancer cells via regulation of Skp2, p53, p21Cip1 and p27Kip1","volume":"6","author":"Lin","year":"2015","journal-title":"Oncotarget"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1186\/1423-0127-21-61","article-title":"Activation of neutral-sphingomyelinase, MAPKs, and p75 NTR-mediating caffeic acid phenethyl ester-induced apoptosis in C6 glioma cells","volume":"21","author":"Tseng","year":"2014","journal-title":"J. Biomed. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2281","DOI":"10.1016\/j.bcp.2003.07.014","article-title":"Involvement of tumor suppressor protein p53 and p38 MAPK in caffeic acid phenethyl ester-induced apoptosis of C6 glioma cells","volume":"66","author":"Lee","year":"2003","journal-title":"Biochem. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1021\/acschembio.5b00945","article-title":"Strategies and approaches of targeting STAT3 for cancer treatment","volume":"11","author":"Furtek","year":"2016","journal-title":"ACS Chem. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1884","DOI":"10.1002\/ijc.24567","article-title":"STAT3 activation contributes directly to Epstein-Barr virus-mediated invasiveness of nasopharyngeal cancer cells in vitro","volume":"125","author":"Lui","year":"2009","journal-title":"Int. J. Cancer"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Pan, Y., Zhou, F., Zhang, R., and Claret, F.X. (2013). Stat3 inhibitor Stattic exhibits potent antitumor activity and induces chemo- and radio-sensitivity in nasopharyngeal carcinoma. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0054565"},{"key":"ref_41","first-page":"716","article-title":"Characterization of seven newly established nasopharyngeal carcinoma cell lines","volume":"68","author":"Lin","year":"1993","journal-title":"Lab. Investig."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1016\/j.canlet.2015.02.034","article-title":"Upregulation of B-cell translocation gene 2 by epigallocatechin-3-gallate via p38 and ERK signaling blocks cell proliferation in human oral squamous cell carcinoma cells","volume":"360","author":"Lee","year":"2015","journal-title":"Cancer Lett."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.canlet.2016.02.056","article-title":"Prostate-derived ets factor represses tumorigenesis and modulates epithelial-to-mesenchymal transition in bladder carcinoma cells","volume":"375","author":"Tsui","year":"2016","journal-title":"Cancer Lett."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/5\/1397\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:03:41Z","timestamp":1760195021000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/5\/1397"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,5,8]]},"references-count":43,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2018,5]]}},"alternative-id":["ijms19051397"],"URL":"https:\/\/doi.org\/10.3390\/ijms19051397","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,5,8]]}}}