title: The fruit juice of Morinda citrifolia (noni) downregulates HIF-1α protein             expression through inhibition of PKB, ERK-1/2, JNK-1 and S6 in manganese-stimulated             A549 human lung cancer cells.
abstract: High exposure of manganese is suggested to be a risk factor for many lung             diseases. Evidence suggests anticancerous and antiangiogenic effects by products             derived from Morinda citrifolia (noni) fruit. In this study, we investigated the             effect of noni fruit juice (NFJ) on the expression of HIF-1α, a tumor angiogenic             transcription factor in manganese-chloride (manganese)-stimulated A549 human lung             carcinoma cells. Treatment with manganese largely induced expression of HIF-1α             protein but did not affect HIF-1α mRNA expression in A549 cells, suggesting the             metal-mediated co- and/or post-translational HIF-1α upregulation. Manganese treatment             also led to increased phosphorylation of extracellular-regulated protein kinase-1/2             (ERK-1/2), c-Jun N-terminal kinase-1 (JNK-1), protein kinase B (PKB), S6 and eukaryotic             translation initiation factor-2α (eIF-2α) in A549 cells. Of note, the exposure             of NFJ inhibited the manganese-induced HIF-1α protein upregulation in a concentration-dependent             manner. Importantly, as assessed by results of pharmacological inhibition and             siRNA transfection studies, the effect of NFJ on HIF-1α protein downregulation             seemed to be largely associated with the ability of NFJ to interfere with the             metal's signaling to activate PKB, ERK-1/2, JNK-1 and S6 in A549 cells. It was             further shown that NFJ could repress the induction of HIF-1α protein by desferoxamine             or interleukin-1β (IL-1β), another HIF-1α inducer in A549 cells. Thus, the present             study provides the first evidence that NFJ has the ability to strongly downregulate             manganese-induced HIF-1α protein expression in A549 human lung cancer cells, which             may suggest the NFJ-mediated beneficial effects on lung pathologies in which manganese             and HIF-1α overexpression play pathogenic roles.
authors.affiliation: Department of Medical Genetic Engineering, Keimyung University School of Medicine, 2800 Dalgubeoldaero, Dalseo-Gu, Daegu 704-701, Republic of Korea. jangbc12@kmu.ac.kr
authors.forename: Byeong-Churl
authors.initials: BC
authors.lastname: Jang
mesh_terms: D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005638:Fruit / Q000737:chemistry*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D008345:Manganese / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048055:Mitogen-Activated Protein Kinase 8 / Q000037:antagonists & inhibitors / Q000378:metabolism; D032066:Morinda / Q000737:chemistry*; D010766:Phosphorylation / Q000187:drug effects; D010936:Plant Extracts / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D055550:Protein Stability / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D015852:Eukaryotic Initiation Factor-2; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010936:Plant Extracts; D008345:Manganese; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048055:Mitogen-Activated Protein Kinase 8