{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T14:47:48Z","timestamp":1781534868667,"version":"3.54.5"},"reference-count":52,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2019,6,4]],"date-time":"2019-06-04T00:00:00Z","timestamp":1559606400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF-2017R1C1B1006072"],"award-info":[{"award-number":["NRF-2017R1C1B1006072"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Incheon National University Research Fund","award":["2016"],"award-info":[{"award-number":["2016"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Chili peppers are one of the most widely consumed spices worldwide. However, research on the health benefits of chili peppers and some of its constituents has raised controversy as to whether chili pepper compounds possess cancer-promoting or cancer-preventive effects. While ample studies have been carried out to examine the effect of capsaicin in carcinogenesis, the chemopreventive effect of other major components in chili pepper, including dihydrocapsaicin, capsiate, and capsanthin, is relatively unclear. Herein, we investigated the inhibitory effect of chili pepper components on malignant cell transformation. Among the tested chili pepper compounds, dihydrocapsaicin displayed the strongest inhibitory activity against epidermal growth factor (EGF)-induced neoplastic transformation. Dihydrocapsaicin specifically suppressed EGF-induced phosphorylations of the p70S6K1-S6 pathway and the expression of c-Fos. A reduction in c-Fos levels by dihydrocapsaicin led to a concomitant downregulation of AP-1 activation. Further analysis of the molecular mechanism responsible for the dihydrocapsaicin-mediated decrease in phospho-p70S6K1, revealed that dihydrocapsaicin can block amino acid-dependent mechanistic targets of rapamycin complex 1 (mTORC1)-p70S6K1-S6 signal activation. Additionally, dihydrocapsaicin was able to selectively augment amino acid deprivation-induced cell death in mTORC1-hyperactive cells. Collectively, dihydrocapsaicin exerted chemopreventive effects through inhibiting amino acid signaling and c-Fos pathways and, thus, might be a promising cancer preventive natural agent.<\/jats:p>","DOI":"10.3390\/nu11061269","type":"journal-article","created":{"date-parts":[[2019,6,5]],"date-time":"2019-06-05T09:37:58Z","timestamp":1559727478000},"page":"1269","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Dihydrocapsaicin Inhibits Epithelial Cell Transformation through Targeting Amino Acid Signaling and c-Fos Expression"],"prefix":"10.3390","volume":"11","author":[{"given":"Ji Su","family":"Lee","sequence":"first","affiliation":[{"name":"Division of Bioengineering, Incheon National University, Incheon 22012, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeong A.","family":"Kim","sequence":"additional","affiliation":[{"name":"Nongshim Co., Ltd, 112, Yeouidaebang-ro, Dongjak-gu, Seoul 07057, Korea"},{"name":"Department of Agricultural Biotechnology, College of Agriculture and Life Sciences, Seoul National University, Seoul 08826, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young Jin","family":"Jang","sequence":"additional","affiliation":[{"name":"Korea Food Research Institute, Wanju-gun, Jeollabuk-do 55365, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongtaek","family":"Oh","sequence":"additional","affiliation":[{"name":"Department of Diagnostics, College of Korean Medicine, Woo-suk University, Wanju-gun, Jeollabuk-do 55338, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanguine","family":"Byun","sequence":"additional","affiliation":[{"name":"Division of Bioengineering, Incheon National University, Incheon 22012, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,6,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"6474","DOI":"10.3390\/molecules19056474","article-title":"Capsaicin and dihydrocapsaicin determination in chili pepper genotypes using ultra-fast liquid chromatography","volume":"19","author":"Usman","year":"2014","journal-title":"Molecules"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ejphar.2010.09.074","article-title":"Recent advances in the study on capsaicinoids and capsinoids","volume":"650","author":"Luo","year":"2011","journal-title":"Eur. J. Pharmacol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1258","DOI":"10.1007\/s13197-014-1260-7","article-title":"Red pepper (Capsicum annuum) carotenoids as a source of natural food colors: Analysis and stability-a review","volume":"52","author":"Arimboor","year":"2015","journal-title":"J. Food Sci. Technol."},{"key":"ref_4","first-page":"524019","article-title":"Antioxidant, antinociceptive, and anti-inflammatory effects of carotenoids extracted from dried pepper (Capsicum annuum L.)","volume":"2012","year":"2012","journal-title":"J. Biomed. Biotechnol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"7583","DOI":"10.1007\/s11033-012-1592-1","article-title":"Expression of TRPV1 in rabbits and consuming hot pepper affects its body weight","volume":"39","author":"Yu","year":"2012","journal-title":"Mol. Biol. Rep."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2809","DOI":"10.1158\/0008-5472.CAN-10-3756","article-title":"The two faces of capsaicin","volume":"71","author":"Bode","year":"2011","journal-title":"Cancer Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"6859","DOI":"10.1158\/0008-5472.CAN-09-4393","article-title":"Cocarcinogenic effect of capsaicin involves activation of EGFR signaling but not TRPV1","volume":"70","author":"Hwang","year":"2010","journal-title":"Cancer Res."},{"key":"ref_8","first-page":"59","article-title":"Carcinogenicity of lifelong administration of capsaicin of hot pepper in mice","volume":"6","author":"Toth","year":"1992","journal-title":"In Vivo"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.ccr.2007.05.008","article-title":"Defining the role of mTOR in cancer","volume":"12","author":"Guertin","year":"2007","journal-title":"Cancer Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1658","DOI":"10.1002\/jcp.24351","article-title":"mTOR signaling for biological control and cancer","volume":"228","author":"Alayev","year":"2013","journal-title":"J. Cell. Physiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.cell.2012.03.017","article-title":"mTOR signaling in growth control and disease","volume":"149","author":"Laplante","year":"2012","journal-title":"Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"317","DOI":"10.2174\/156800907780809723","article-title":"AP-1 a target for cancer prevention","volume":"7","author":"Matthews","year":"2007","journal-title":"Curr. Cancer Drug Targets"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/1040-8428(94)90021-3","article-title":"c-fos proto-oncogene regulation and function","volume":"17","author":"Piechaczyk","year":"1994","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"65946","DOI":"10.18632\/oncotarget.11779","article-title":"c-Fos over-expression promotes radioresistance and predicts poor prognosis in malignant glioma","volume":"7","author":"Liu","year":"2016","journal-title":"Oncotarget"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1097\/00000658-199506000-00010","article-title":"Oncogene protein co-expression. Value of Ha-ras, c-myc, c-fos, and p53 as prognostic discriminants for breast carcinoma","volume":"221","author":"Bland","year":"1995","journal-title":"Ann. Surg."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1038\/sj.bjc.6604650","article-title":"C-Fos expression is a molecular predictor of progression and survival in epithelial ovarian carcinoma","volume":"99","author":"Mahner","year":"2008","journal-title":"Br. J. Cancer"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"15615","DOI":"10.1038\/s41598-018-33689-0","article-title":"c-Fos induces chondrogenic tumor formation in immortalized human mesenchymal progenitor cells","volume":"8","author":"Abarrategi","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1016\/0092-8674(95)90469-7","article-title":"c-fos is required for malignant progression of skin tumors","volume":"82","author":"Saez","year":"1995","journal-title":"Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3120","DOI":"10.1158\/1078-0432.CCR-16-2811","article-title":"Involvement of c-Fos in the Promotion of Cancer Stem-like Cell Properties in Head and Neck Squamous Cell Carcinoma","volume":"23","author":"Muhammad","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2124","DOI":"10.1021\/acs.jnatprod.7b00433","article-title":"Caffeic Acid Phenethyl Ester from the Twigs of Cinnamomum cassia Inhibits Malignant Cell Transformation by Inducing c-Fos Degradation","volume":"80","author":"Shin","year":"2017","journal-title":"J. Nat. Prod."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1073\/pnas.91.2.609","article-title":"Blocking of tumor promoter-induced AP-1 activity inhibits induced transformation in JB6 mouse epidermal cells","volume":"91","author":"Dong","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2415","DOI":"10.1158\/0008-5472.CAN-09-4093","article-title":"Luteolin inhibits protein kinase C(epsilon) and c-Src activities and UVB-induced skin cancer","volume":"70","author":"Byun","year":"2010","journal-title":"Cancer Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.molcel.2012.10.003","article-title":"Metabolic stress controls mTORC1 lysosomal localization and dimerization by regulating the TTT-RUVBL1\/2 complex","volume":"49","author":"Kim","year":"2013","journal-title":"Mol. Cell"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2315","DOI":"10.1038\/nprot.2006.339","article-title":"Clonogenic assay of cells in vitro","volume":"1","author":"Franken","year":"2006","journal-title":"Nat. Protoc."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1586\/14737140.3.3.367","article-title":"Targeting epidermal growth factor receptor: Novel therapeutics in the management of cancer","volume":"3","author":"Khalil","year":"2003","journal-title":"Expert Rev. Anticancer Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1002\/mc.10140","article-title":"Involvement of the Akt\/mTOR pathway on EGF-induced cell transformation","volume":"38","author":"Nomura","year":"2003","journal-title":"Mol. Carcinog."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0959-8049(01)00230-1","article-title":"The EGFR family and its ligands in human cancer. signalling mechanisms and therapeutic opportunities","volume":"37","author":"Yarden","year":"2001","journal-title":"Eur. J. Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1517\/14728222.2011.648617","article-title":"Targeting the EGFR signaling pathway in cancer therapy","volume":"16","author":"Seshacharyulu","year":"2012","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/bs.ircmb.2014.10.001","article-title":"Epidermal growth factor signaling in transformed cells","volume":"314","author":"Lindsey","year":"2015","journal-title":"Int. Rev. Cell Mol. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Wee, P., and Wang, Z. (2017). Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways. Cancers, 9.","DOI":"10.3390\/cancers9050052"},{"key":"ref_31","first-page":"4424","article-title":"Transcription of cyclooxygenase-2 is enhanced in transformed mammary epithelial cells","volume":"56","author":"Subbaramaiah","year":"1996","journal-title":"Cancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1126\/science.1207056","article-title":"mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase","volume":"334","author":"Zoncu","year":"2011","journal-title":"Science"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.cell.2010.02.024","article-title":"Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids","volume":"141","author":"Sancak","year":"2010","journal-title":"Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1016\/j.tcb.2014.03.003","article-title":"Regulation of mTORC1 by amino acids","volume":"24","author":"Sabatini","year":"2014","journal-title":"Trends Cell Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4198","DOI":"10.3892\/mmr.2016.5784","article-title":"Capsaicin and dihydrocapsaicin induce apoptosis in human glioma cells via ROS and Ca2+-mediated mitochondrial pathway","volume":"14","author":"Xie","year":"2016","journal-title":"Mol. Med. Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.4161\/auto.6886","article-title":"Dihydrocapsaicin (DHC), a saturated structural analog of capsaicin, induces autophagy in human cancer cells in a catalase-regulated manner","volume":"4","author":"Oh","year":"2008","journal-title":"Autophagy"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.freeradbiomed.2010.04.014","article-title":"Selective induction of catalase-mediated autophagy by dihydrocapsaicin in lung cell lines","volume":"49","author":"Choi","year":"2010","journal-title":"Free Radic. Biol. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"23553","DOI":"10.1074\/jbc.M115.662445","article-title":"Identification of a Dual Inhibitor of Janus Kinase 2 (JAK2) and p70 Ribosomal S6 Kinase1 (S6K1) Pathways","volume":"290","author":"Byun","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"14246","DOI":"10.1074\/jbc.M110.147348","article-title":"7,3\u2019,4\u2019-Trihydroxyisoflavone, a metabolite of the soy isoflavone daidzein, suppresses ultraviolet B-induced skin cancer by targeting Cot and MKK4","volume":"286","author":"Lee","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"15115","DOI":"10.1073\/pnas.1212802109","article-title":"Synthesis, cellular evaluation, and mechanism of action of piperlongumine analogs","volume":"109","author":"Adams","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/0092-8674(84)90073-4","article-title":"c-fos protein can induce cellular transformation: A novel mechanism of activation of a cellular oncogene","volume":"36","author":"Miller","year":"1984","journal-title":"Cell"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1158\/1078-0432.CCR-09-0234","article-title":"The role of the Akt\/mTOR pathway in tobacco carcinogen-induced lung tumorigenesis","volume":"16","author":"Memmott","year":"2010","journal-title":"Clin. Cancer Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3254","DOI":"10.1038\/onc.2012.338","article-title":"The mTOR inhibitor rapamycin opposes carcinogenic changes to epidermal Akt1\/PKBalpha isoform signaling","volume":"32","author":"Sully","year":"2013","journal-title":"Oncogene"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.1093\/carcin\/bgw086","article-title":"mTOR inhibition prevents rapid-onset of carcinogen-induced malignancies in a novel inducible HPV-16 E6\/E7 mouse model","volume":"37","author":"Amornphimoltham","year":"2016","journal-title":"Carcinogenesis"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1158\/1940-6207.CAPR-08-0147","article-title":"Targeting mammalian target of rapamycin by rapamycin prevents tumor progression in an oral-specific chemical carcinogenesis model","volume":"2","author":"Czerninski","year":"2009","journal-title":"Cancer Prev. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1038\/nature10912","article-title":"The translational landscape of mTOR signalling steers cancer initiation and metastasis","volume":"485","author":"Hsieh","year":"2012","journal-title":"Nature"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1016\/j.celrep.2017.10.029","article-title":"The mTORC1 Signaling Network Senses Changes in Cellular Purine Nucleotide Levels","volume":"21","author":"Hoxhaj","year":"2017","journal-title":"Cell Rep."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"19705","DOI":"10.1074\/jbc.C110.102483","article-title":"Regulation of mTORC1 by the Rab and Arf GTPases","volume":"285","author":"Li","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_49","first-page":"837","article-title":"Anticancer Properties of Capsaicin against Human Cancer","volume":"36","author":"Clark","year":"2016","journal-title":"Anticancer Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1002\/em.2860070609","article-title":"Mutagenicity of chili extract and capsaicin in short-term tests","volume":"7","author":"Nagabhushan","year":"1985","journal-title":"Environ. Mutagen."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1016\/j.foodchem.2016.11.074","article-title":"Contents of capsaicinoids in chillies grown in Denmark","volume":"221","author":"Duelund","year":"2017","journal-title":"Food Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.1021\/jf010527a","article-title":"Pungency in paprika (Capsicum annuum). 1. Decrease of capsaicinoid content following cellular disruption","volume":"50","author":"Hiepler","year":"2002","journal-title":"J. Agric. Food Chem."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/11\/6\/1269\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:56:08Z","timestamp":1760187368000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/11\/6\/1269"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,6,4]]},"references-count":52,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2019,6]]}},"alternative-id":["nu11061269"],"URL":"https:\/\/doi.org\/10.3390\/nu11061269","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,6,4]]}}}