title: CoCl2-induced HIF-1alpha expression correlates with proliferation and apoptosis in MKN-1 cells: a possible role for the PI3K/Akt pathway.
abstract: The exact mechanism behind the effect of hypoxia-inducible factor-1alpha (HIF-1alpha) on the proliferation and/or apoptosis of carcinoma cells is still a matter of debate. We treated a human gastric carcinoma cell line, MKN-1 (mutant P53), with 500 microM CoCl(2). A dual-phase pattern of HIF-1alpha expression with an increase until 4 h followed by a decrease until 36 h was observed. Immunocytochemistry showed that nuclear translocation was maximal at 4 h of treatment, while trypan blue staining showed a dual-phase pattern. Instead of G1/S arrest, FACS showed an increase in the pre-G1 fraction and G(2)/M arrest that correlated with Cyclin-B1, SKP-2 and P27 expression. Starting at 6 h, the apoptotic index increased in a time-dependent manner, in correlation with the expression of HIF-1alpha, Bcl-2, Bcl-xL, Bax and cleaved-Caspase-9. Phosphorylation of Akt was inhibited by CoCl(2) treatment and LY294002 treatment inhibited HIF-1alpha expression in a dose-dependent manner. These results suggested that the alteration of CoCl(2)-induced HIF-1alpha expression correlated with proliferation and apoptosis in MKN-1 cells. A possible role for the PI3K/Akt pathway was indicated in this model of hypoxia.
authors.affiliation: Department of Microbiology and Pathology, Division of Organ Pathology, Faculty of Medicine, Tottori University, Tottori, Japan.
authors.forename: Tonang Dwi
authors.initials: TD
authors.lastname: Ardyanto
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Osaki
authors.forename: Naruo
authors.initials: N
authors.lastname: Tokuyasu
authors.forename: Yumi
authors.initials: Y
authors.lastname: Nagahama
authors.forename: Hisao
authors.initials: H
authors.lastname: Ito
mesh_terms: D016587:Antimutagenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D015687:Cell Hypoxia; D049109:Cell Proliferation / Q000187:drug effects*; D058534:Class I Phosphatidylinositol 3-Kinases; D003035:Cobalt / Q000494:pharmacology*; D019926:Cyclin B / Q000378:metabolism; D056744:Cyclin B1; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000378:metabolism; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D016587:Antimutagenic Agents; C534699:CCNB1 protein, human; D019926:Cyclin B; D056744:Cyclin B1; D051793:Hypoxia-Inducible Factor 1; D019253:Proto-Oncogene Proteins c-bcl-2; D044786:S-Phase Kinase-Associated Proteins; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003035:Cobalt; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D051057:Proto-Oncogene Proteins c-akt; C506433:CASP9 protein, human; D053453:Caspase 9; D020169:Caspases; C018021:cobaltous chloride