title: Ginsenoside Rg3 suppresses FUT4 expression through inhibiting NF-κB/p65 signaling pathway to promote melanoma cell death.
abstract: Abnormal glycosylation is catalyzed by the specific glycosyltransferases and correlates with tumor cell apoptosis. Increased fucosyltransferase IV (FUT4) is seen in many types of cancer, and manipulating FUT4 expression through specific signaling pathway inhibits cell growth and induces apoptosis. NF-κB is known playing a vital role to control cell growth and apoptosis. Ginsenoside Rg3 is an herbal medicine with strong antitumor activity through inhibiting tumor growth and promoting tumor cell death. However, whether Rg3-induced inhibition on tumor development involves reduced NF-κB signaling and FUT4 expression remains unknown. In the present study, we found that Rg3 suppressed FUT4 expression by abrogating the binding of NF-κB to FUT4 promoter through inhibiting the expression of signaling molecules of NF-κB pathway, reducing NF-κB DNA binding activity and NF-κB transcription activity. NF-κB inhibitor (Bay 11-7082) or knocking down p65 expression by p65 siRNA also led to a significant decreased FUT4 expression. In addition, Rg3 induced apoptosis by activating both extrinsic and intrinsic apoptotic pathways. Moreover, in a xenograft mouse model, Rg3 downregulated FUT4 and NF-κB/p65 expression and suppressed melanoma cell growth and induced apoptosis without any noticeable toxicity. In conclusion, Rg3 induces tumor cell apoptosis correlated with its inhibitory effect on NF-κB signaling pathway-mediated FUT4 expression. Results suggest Rg3 might be a novel therapy agent for melanoma treatment.
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China.
authors.forename: Xiu
authors.initials: X
authors.lastname: Shan
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China.
authors.forename: Li Li
authors.initials: LL
authors.lastname: Tian
authors.affiliation: Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, Department of Biochemistry and Molecular Biology, Dalian Medical University, Dalian, Liaoning 116044, P.R. China.
authors.forename: Yu Mei
authors.initials: YM
authors.lastname: Zhang
authors.affiliation: Department of Dermatology, Northwestern University's Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Xiao Qi
authors.initials: XQ
authors.lastname: Wang
authors.affiliation: Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, Department of Biochemistry and Molecular Biology, Dalian Medical University, Dalian, Liaoning 116044, P.R. China.
authors.forename: Qiu
authors.initials: Q
authors.lastname: Yan
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China.
authors.forename: Ji Wei
authors.initials: JW
authors.lastname: Liu
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000494:pharmacology; D017209:Apoptosis; D001665:Binding Sites / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005647:Fucosyltransferases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D036145:Ginsenosides / Q000008:administration & dosage* / Q000494:pharmacology; D006801:Humans; D016256:Lewis X Antigen / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D036145:Ginsenosides; D016256:Lewis X Antigen; D016328:NF-kappa B; C097367:ginsenoside Rg3; C066693:FUT4 protein, human; D005647:Fucosyltransferases