{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T10:18:07Z","timestamp":1790072287793,"version":"4.0.1"},"reference-count":51,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2015,11,27]],"date-time":"2015-11-27T00:00:00Z","timestamp":1448582400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Apigenin, a nonmutagenic flavonoid, has been found to have antitumor properties and is therefore particularly relevant for the development of chemotherapeutic agents for cancers. In this study, time- and dose-dependent cell viability and cytotoxicity were assessed to determine the effects of apigenin on A2058 and A375 melanoma cells. Melanoma cells were pretreated with different concentrations of apigenin and analyzed for morphological changes, anoikis induction, cell migration, and levels of proteins associated with apoptosis. Apigenin reduced integrin protein levels and inhibited the phosphorylation of focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK1\/2), which induce anoikis in human cutaneous melanoma cells. Apigenin exhibited dose-dependent inhibition of melanoma cell migration, unlike untreated controls. Furthermore, apigenin treatment increased apoptotic factors such as caspase-3 and cleaved poly(ADP-ribose) polymerase in a dose-dependent manner, demonstrating the metastasis of melanoma cells. Our results provide a new insight into the mechanisms by which apigenin prevents melanoma metastasis by sensitizing anoikis induced by the loss of integrin proteins in the FAK\/ERK1\/2 signaling pathway. These findings elucidate the related mechanisms and suggest the potential of apigenin in developing clinical treatment strategies against malignant melanoma.<\/jats:p>","DOI":"10.3390\/molecules201219752","type":"journal-article","created":{"date-parts":[[2015,11,27]],"date-time":"2015-11-27T10:25:29Z","timestamp":1448619929000},"page":"21157-21166","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":59,"title":["Apigenin Attenuates Melanoma Cell Migration by Inducing Anoikis through Integrin and Focal Adhesion Kinase Inhibition"],"prefix":"10.3390","volume":"20","author":[{"given":"Md.","family":"Hasnat","sequence":"first","affiliation":[{"name":"Department of Life Sciences, College of Biomedical &amp; Health Science, Konkuk University, Chungju 380-701, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehnaz","family":"Pervin","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, College of Biomedical &amp; Health Science, Konkuk University, Chungju 380-701, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji","family":"Lim","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, College of Biomedical &amp; Health Science, Konkuk University, Chungju 380-701, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9618-5956","authenticated-orcid":false,"given":"Beong","family":"Lim","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, College of Biomedical &amp; Health Science, Konkuk University, Chungju 380-701, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2015,11,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2375","DOI":"10.1016\/j.ejca.2012.06.013","article-title":"Diagnosis and treatment of melanoma. European consensus-based interdisciplinary guideline\u2014Update 2012","volume":"48","author":"Garbe","year":"2012","journal-title":"Eur. J. Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"267","DOI":"10.3233\/CBM-2011-0164","article-title":"The molecular pathology of cutaneous melanoma","volume":"9","author":"Bogenrieder","year":"2010","journal-title":"Cancer Biomark."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1023\/A:1015547830323","article-title":"Integrins and prostate cancer metastases","volume":"20","author":"Fornaro","year":"2001","journal-title":"Cancer Metastasis Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1002\/path.3000","article-title":"Anoikis: An emerging hallmark in health and diseases","volume":"226","author":"Taddei","year":"2012","journal-title":"J. Pathol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1097\/00062752-199901000-00007","article-title":"Integrins and signal transduction","volume":"6","author":"Dedhar","year":"1999","journal-title":"Curr. Opin. Hematol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1126\/science.285.5430.1028","article-title":"Integrin signaling","volume":"285","author":"Giancotti","year":"1999","journal-title":"Science"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1146\/annurev.pharmtox.42.090401.151133","article-title":"Signal transduction by cell adhesion receptors and the cytoskeleton: Functions of integrins, cadherins, selectins, and immunoglobulin-superfamily members","volume":"42","author":"Juliano","year":"2002","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1023\/A:1006304806799","article-title":"Cell adhesion molecules in the development and progression of malignant melanoma","volume":"18","author":"Johnson","year":"1999","journal-title":"Cancer Metastasis Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1126\/science.7716514","article-title":"Integrins and signal transduction pathways: The road taken","volume":"268","author":"Clark","year":"1995","journal-title":"Science"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1146\/annurev.cb.11.110195.003001","article-title":"Integrins: Emerging paradigms of signal transduction","volume":"11","author":"Schwartz","year":"1995","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1016\/0140-6736(93)92881-S","article-title":"Expression of focal adhesion kinase gene and invasive cancer","volume":"342","author":"Weiner","year":"1993","journal-title":"Lancet"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"298","DOI":"10.3346\/jkms.2007.22.2.298","article-title":"Sphingosine 1-phosphate triggers apoptotic signal for B16 melanoma cells via ERK and caspase activation","volume":"22","author":"Shin","year":"2007","journal-title":"J. Korean Med. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.bcp.2011.11.008","article-title":"Berberine-induced AMPK activation inhibits the metastatic potential of melanoma cells via reduction of ERK activity and COX-2 protein expression","volume":"83","author":"Kim","year":"2012","journal-title":"Biochem. Pharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1016\/j.fct.2010.11.030","article-title":"Rosmanol potently induces apoptosis through both the mitochondrial apoptotic pathway and death receptor pathway in human colon adenocarcinoma COLO 205 cells","volume":"49","author":"Cheng","year":"2011","journal-title":"Food Chem. Toxicol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1080\/09553000801902125","article-title":"Effect of neutron capture therapy on the cell cycle of human squamous cell carcinoma cells","volume":"84","author":"Kamida","year":"2008","journal-title":"Int. J. Radiat. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1158\/1535-7163.MCT-11-0343","article-title":"Apigenin induces apoptosis in human leukemiacells and exhibits anti-leukemic activity in vivo","volume":"11","author":"Budhraja","year":"2012","journal-title":"Mol. Cancer Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1093\/carcin\/bgs358","article-title":"Src kinase is a direct target of apigenin against UVB-induced skininflammation","volume":"34","author":"Byun","year":"2013","journal-title":"Carcinogenesis"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.maturitas.2006.06.015","article-title":"The flavonoid apigenin inhibits the proliferation of prostatic stromal cells via the MAPK-pathway and cell-cycle arrest in G1\/S","volume":"55","author":"Bektic","year":"2006","journal-title":"Maturitas"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1207\/S15327914nc391_19","article-title":"Apigenin acts on the tumor cell invasion process and regulates protease production","volume":"39","author":"Lindenmeyer","year":"2001","journal-title":"Nutr. Cancer"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1124\/mol.105.011254","article-title":"Apigenin inhibits expression of vascular endothelial growth factor and angiogenesis in human lung cancer cells: Implication of chemoprevention of lung cancer","volume":"68","author":"Liu","year":"2005","journal-title":"Mol. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1096\/fj.04-2175com","article-title":"Apigenin inhibits VEGF and HIF-1 expression via PI3K\/AKT\/p70S6K1 and HDM2\/p53 pathways","volume":"19","author":"Fang","year":"2005","journal-title":"FASEB J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1002\/(SICI)1097-0215(20000301)85:5<691::AID-IJC15>3.0.CO;2-Q","article-title":"Apigenin inhibits endothelial-cell proliferation in G(2)\/M phase whereas it stimulates smooth-muscle cells by inhibiting P21 and P27 expression","volume":"85","author":"Trochon","year":"2000","journal-title":"Int. J. Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1477","DOI":"10.1093\/jn\/136.6.1477","article-title":"Flavonoids and vitamin E reduce the release of the angiogenic peptide vascular endothelial growth factor from human tumor cells","volume":"136","author":"Schindler","year":"2006","journal-title":"J. Nutr."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1016\/j.fct.2013.09.037","article-title":"Efficacy of PLGA-loaded apigenin nanoparticles in Benzo[a]pyrene and ultraviolet-B induced skin cancer of mice: Mitochondria mediated apoptotic signalling cascades","volume":"62","author":"Das","year":"2013","journal-title":"Food Chem. Toxicol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/0959-8049(95)00540-4","article-title":"Inhibitions of protein kinase C and proto-oncogene expressions in NIH 3T3 cells by apigenin","volume":"32","author":"Huang","year":"1996","journal-title":"Eur. J. Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1649","DOI":"10.1016\/S0006-2952(97)82453-7","article-title":"Relationship between flavonoid structure and inhibition of phosphatidylinositol 3-kinase: A comparison with tyrosine kinase and protein kinase C inhibition","volume":"53","author":"Agullo","year":"1997","journal-title":"Biochem. Pharmacol."},{"key":"ref_27","first-page":"413","article-title":"Apigenin inhibits growth and induces G2\/M arrest by modulating cyclin-CDK regulators and ERK MAP kinase activation in breast carcinoma cells","volume":"21","author":"Yin","year":"2001","journal-title":"Anticancer Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.yexcr.2004.05.006","article-title":"Unbalanced activation of ERK1\/2 and MEK1\/2 in apigenin-induced HeLa cell death","volume":"299","author":"Llorens","year":"2004","journal-title":"Exp. Cell Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.4161\/cc.6.9.4146","article-title":"Apigenin-induced cell cycle arrest is mediated by modulation of MAPK, PI3K-Akt, and loss of cyclin D1 associated retinoblastoma dephosphorylation in human prostate cancer cells","volume":"6","author":"Shukla","year":"2007","journal-title":"Cell Cycle"},{"key":"ref_30","first-page":"6757","article-title":"Integrin distribution in malignant melanoma: Association of the beta 3 subunit with tumor progression","volume":"50","author":"Albelda","year":"1990","journal-title":"Cancer Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1016\/S0046-8177(99)90202-2","article-title":"Progression-related expression of beta3 integrin in melanomas and nevi","volume":"30","author":"Elenitsas","year":"1999","journal-title":"Hum Pathol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1016\/0092-8674(93)90509-O","article-title":"Bcl-2 heterodimerizes in vivo with a conversed homolog, Bax, that accelerates programmed cell death","volume":"74","author":"Oltvai","year":"1993","journal-title":"Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"28379","DOI":"10.1074\/jbc.274.40.28379","article-title":"Cleavage of automodified poly(ADP-ribose) polymerase during apoptosis","volume":"274","author":"Germain","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1146\/annurev.cellbio.21.012704.131040","article-title":"Mechanisms of apoptosis through structural biology","volume":"21","author":"Yan","year":"2005","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e94298","DOI":"10.1371\/journal.pone.0094298","article-title":"Piperine Causes G1 Phase Cell Cycle Arrest and Apoptosis in Melanoma Cells through Checkpoint Kinase-1 Activation","volume":"9","author":"Fofaria","year":"2014","journal-title":"PLoS ONE"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1038\/nrclinonc.2011.201","article-title":"Melanoma in 2011: A new paradigm tumor for drug development","volume":"10","author":"Eggermont","year":"2012","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/carcin\/bgp220","article-title":"Epigenetics in cancer","volume":"31","author":"Sharma","year":"2009","journal-title":"Carcinogenesis"},{"key":"ref_38","first-page":"233","article-title":"Apigenin and cancer chemoprevention: Progress, potential and promise (review)","volume":"30","author":"Patel","year":"2007","journal-title":"Int. J. Oncol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1038\/nrm1490","article-title":"Integrin signalling during tumour progression","volume":"5","author":"Guo","year":"2004","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1016\/0046-8177(92)90034-Z","article-title":"Integrins and their accessory adhesion molecules in mammary carcinomas: Loss of polarization in poorly differentiated tumors","volume":"23","author":"Pignatelli","year":"1992","journal-title":"Hum. Pathol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1016\/0955-0674(94)90097-3","article-title":"Focal adhesion kinase and associated proteins","volume":"6","author":"Schaller","year":"1994","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"705","DOI":"10.2741\/1115","article-title":"Focal adhesion kinase in cancer","volume":"8","author":"Hecker","year":"2003","journal-title":"Front. Biosci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"22631","DOI":"10.1074\/jbc.M210876200","article-title":"Bombesin, lysophosphatidic acid, and epidermal growth factor rapidly stimulate focal adhesion kinase phosphorylation at Ser\u2013910: Requirement for ERK activation","volume":"278","author":"Salazar","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1038\/35010517","article-title":"FAK integrates growth-factor and integrin signals to promote cell migration","volume":"2","author":"Sieg","year":"2000","journal-title":"Nat. Cell Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1911","DOI":"10.1126\/science.1072682","article-title":"Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases","volume":"298","author":"Johnson","year":"2002","journal-title":"Science"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1083\/jcb.124.4.619","article-title":"Disruption of epithelial cell-matrix interactions induce apoptosis","volume":"124","author":"Frisch","year":"1994","journal-title":"J. Cell Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"20049","DOI":"10.1074\/jbc.274.29.20049","article-title":"Suicidal tendencies: Apoptotic cell death by caspase family proteinases","volume":"274","author":"Wolf","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1111\/j.1471-4159.2004.02774.x","article-title":"Chemotherapy-induced cell death in primary cerebellar granule neurons but not in astrocytes: In vitro paradigm of differential neurotoxicity","volume":"91","author":"Wick","year":"2004","journal-title":"J. Neurochem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/S0014-5793(99)00984-9","article-title":"Caspases-3 and -7 are activated in goniothalamin-induced apoptosis in human Jurkat T-cells","volume":"456","author":"Osman","year":"1999","journal-title":"FEBS Lett."},{"key":"ref_50","first-page":"3200","article-title":"Cyclin D1 is a candidate oncogene in cutaneous melanoma","volume":"62","author":"Sauter","year":"2002","journal-title":"Cancer Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1111\/j.1751-1097.2012.01100.x","article-title":"Tualang honey protects keratinocytes from ultraviolet radiation-induced inflammation and DNA damage","volume":"88","author":"Ahmad","year":"2012","journal-title":"Photochem. Photobiol."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/20\/12\/19752\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T20:52:55Z","timestamp":1760215975000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/20\/12\/19752"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,11,27]]},"references-count":51,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2015,12]]}},"alternative-id":["molecules201219752"],"URL":"https:\/\/doi.org\/10.3390\/molecules201219752","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,11,27]]}}}