title: Houttuynia cordata Thunb Promotes Activation of HIF-1A-FOXO3 and MEF2A Pathways to Induce Apoptosis in Human HepG2 Hepatocellular Carcinoma Cells.
abstract: Houttuynia cordata Thunb ( H cordata), a medicinal plant, has anticancer activity, as it inhibits cell growth and induces cell apoptosis in cancer. However, the potential anti-cancer activity and mechanism of H cordata for human liver cancer cells is not well understood. Recently, we identified hypoxia-inducible factor (HIF)-1A, Forkhead box (FOX)O3, and MEF2A as proapoptotic factors induced by H cordata, suggesting that HIF-1A, FOXO3, and MEF2A contribute to the apoptosis of HepG2 hepatocellular carcinoma cells. FOXO3 transcription factors regulate target genes involved in apoptosis. H cordata significantly increased the mRNA and protein expression of HIF-1A and FOXO3 and stimulated MEF2A expression in addition to increased apoptosis in HepG2 cells within 24 hours. Therefore, we determined the potential role of FOXO3 on apoptosis and on H cordata-induced MEF2A in HepG2 cells. HIF-1A silencing by siRNA attenuated MEF2A and H cordata-mediated FOXO3 upregulation in HepG2 cells. Furthermore, H cordata-mediated MEF2A expression enhanced caspase-3 and caspase-7, which were abolished on silencing FOXO3 with siRNA. In addition, H cordata inhibited growth of human hepatocellular carcinoma xenografts in nude mice. Taken together, our results demonstrate that H cordata enhances HIF-1A/FOXO3 signaling, leading to MEF2A upregulation in HepG2 cells, and in parallel, it disturbs the expression of Bcl-2 family proteins (Bax, Bcl-2, and Bcl-xL), which results in apoptosis. Taken together, these findings demonstrate that H cordata promotes the activation of HIF-1A-FOXO3 and MEF2A pathways to induce apoptosis in human HepG2 hepatocellular carcinoma cells and is, therefore, a promising candidate for antitumor drug development.
authors.affiliation: 1 Daejeon Oriental Hospital of Daejeon University, Daejeon, Republic of Korea.
authors.forename: Jung Min
authors.initials: JM
authors.lastname: Kim
authors.affiliation: 2 Korea University College of Medicine, Seoul, Republic of Korea.
authors.forename: In-Hu
authors.initials: IH
authors.lastname: Hwang
authors.affiliation: 3 Korea Basic Science Institute, Daejeon, Republic of Korea.
authors.forename: Ik-Soon
authors.initials: IS
authors.lastname: Jang
authors.affiliation: 3 Korea Basic Science Institute, Daejeon, Republic of Korea.
authors.forename: Min
authors.initials: M
authors.lastname: Kim
authors.affiliation: 4 Hoseo University, Asan, Republic of Korea.
authors.forename: In Seok
authors.initials: IS
authors.lastname: Bang
authors.affiliation: 5 Woosuk University, Jeonju, Jeonbuk, Republic of Korea.
authors.forename: Soo Jung
authors.initials: SJ
authors.lastname: Park
authors.affiliation: 6 Chonbuk National University, Jeonju, Republic of Korea.
authors.forename: Yun-Jo
authors.initials: YJ
authors.lastname: Chung
authors.affiliation: 7 Wonkwang University, Iksan, Republic of Korea.
authors.forename: Jong-Cheon
authors.initials: JC
authors.lastname: Joo
authors.affiliation: 2 Korea University College of Medicine, Seoul, Republic of Korea.
authors.forename: Min-Goo
authors.initials: MG
authors.lastname: Lee
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000071316:Forkhead Box Protein O3 / Q000378:metabolism*; D056945:Hep G2 Cells; D052859:Houttuynia / Q000737:chemistry*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D064326:MEF2 Transcription Factors / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010936:Plant Extracts / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D064326:MEF2 Transcription Factors; C578035:MEF2A protein, human; D010936:Plant Extracts; D019253:Proto-Oncogene Proteins c-bcl-2
keywords: FOXO3; HIF-1A; HepG2; Houttuynia cordata; MEF2A; apoptosis