title: Synergistic up-regulation of Hexokinase-2, glucose transporters and angiogenic factors in pancreatic cancer cells by glucose deprivation and hypoxia.
abstract: There is accumulating evidence demonstrating that HIF-1 functions as a key regulator of the adaptation responses to hypoxia in cancer tissues. To this evidence, we add that adaptation responses to glucose deprivation plus hypoxia are also necessary for the survival of tumor cells in the tumor microenvironment as cancer tissues are exposed to glucose deprivation as well as hypoxia. We found that adrenomedullin (AM), VEGF, Glut-1, Glut-3, and Hexokinase-2 among 45 hypoxia-inducible genes investigated were expressed at higher levels under glucose-deprived hypoxic conditions than under hypoxic conditions. Glucose deprivation activated the AMPK under normoxia and hypoxia. Compound C, an inhibitor of AMPK, suppressed the expressions of AM and VEGF which had already been enhanced under glucose-deprived hypoxic conditions. siRNAs for both AMPKalpha1 and AMPKalpha2 suppressed the expressions of AM and VEGF. HIF-1alpha protein level and the transcriptional activity of HIF-1 under glucose-deprived hypoxic conditions were thus found to be similar to those under hypoxic conditions. Furthermore, tumor cells in 15 out of 20 human pancreatic cancer tissue specimens were stained by anti-phospho-AMPKalpha antibody. Our results thus suggest that the enhanced expressions of those genes mediated by the activation of AMPK and HIF-1 therefore play a pivotal role in the tumor formation of pancreatic cancers.
authors.affiliation: Department of Pathological Oncology, Division of Cancer Medicine, Hokkaido University Graduate School of Medicine, Japan.
authors.forename: Mitsuteru
authors.initials: M
authors.lastname: Natsuizaka
authors.forename: Mariko
authors.initials: M
authors.lastname: Ozasa
authors.forename: Stephanie
authors.initials: S
authors.lastname: Darmanin
authors.forename: Masaki
authors.initials: M
authors.lastname: Miyamoto
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kondo
authors.forename: Suguru
authors.initials: S
authors.lastname: Kamada
authors.forename: Masanobu
authors.initials: M
authors.lastname: Shindoh
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Higashino
authors.forename: Wakako
authors.initials: W
authors.lastname: Suhara
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Koide
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Aita
authors.forename: Koji
authors.initials: K
authors.lastname: Nakagawa
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kondo
authors.forename: Masahiro
authors.initials: M
authors.lastname: Asaka
authors.forename: Futoshi
authors.initials: F
authors.lastname: Okada
authors.forename: Masanobu
authors.initials: M
authors.lastname: Kobayashi
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D014408:Biomarkers, Tumor / Q000096:biosynthesis; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D005947:Glucose / Q000502:physiology*; D051246:Glucose Transport Proteins, Facilitative / Q000096:biosynthesis*; D006593:Hexokinase / Q000096:biosynthesis*; D006801:Humans; D000860:Hypoxia; D051793:Hypoxia-Inducible Factor 1 / Q000096:biosynthesis*; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000378:metabolism*; D010766:Phosphorylation; D011494:Protein Kinases / Q000096:biosynthesis* / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; D051246:Glucose Transport Proteins, Facilitative; D051793:Hypoxia-Inducible Factor 1; D034741:RNA, Small Interfering; D011494:Protein Kinases; D006593:Hexokinase; D000091162:AMP-Activated Protein Kinase Kinases; D005947:Glucose