Synergistic up-regulation of Hexokinase-2, glucose transporters and angiogenic factors in pancreatic cancer cells by glucose deprivation and hypoxia.
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.
Natsuizaka
Mitsuteru
M
Department of Pathological Oncology, Division of Cancer Medicine, Hokkaido University Graduate School of Medicine, Japan.
Ozasa
Mariko
M
Darmanin
Stephanie
S
Miyamoto
Masaki
M
Kondo
Satoshi
S
Kamada
Suguru
S
Shindoh
Masanobu
M
Higashino
Fumihiro
F
Suhara
Wakako
W
Koide
Hideyuki
H
Aita
Kiyoshi
K
Nakagawa
Koji
K
Kondo
Takeshi
T
Asaka
Masahiro
M
Okada
Futoshi
F
Kobayashi
Masanobu
M
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
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