Constitutive expression of hypoxia-inducible factor-1alpha renders pancreatic cancer cells resistant to apoptosis induced by hypoxia and nutrient deprivation.
Hypovasculature is an outstanding characteristic of pancreatic cancers in imaging diagnosis, suggesting that blood supply is poor in pancreatic cancer tissues. Despite poor blood supply, pancreatic cancer cells survive and proliferate in severe hypoxia and nutrient deprivation. To demonstrate how pancreatic cancer cells adapt themselves to hypoxia and nutrient deprivation, we investigated the expression of hypoxia-inducible factor 1alpha (HIF-1alpha) protein and HIF-1-inducible genes in human pancreatic cancer cell lines in comparison with other cancer cell lines. We found that HIF-1alpha protein was constitutively expressed in 15 of 20 pancreatic cancer cell lines (75%) but in none of other cancer cell lines tested in this study. The cells with constitutive expression of HIF-1alpha were more resistant to apoptosis induced by hypoxia and glucose deprivation than those without constitutive expression of HIF-1alpha. Transfection with HIF-1alpha transformed the latter cells resistant to apoptosis and increased in vivo tumorigenicity. Furthermore, anaerobic metabolism-associated genes, Glut1 and aldolase A, were more highly expressed in the cells with constitutive expression of HIF-1alpha than in the cells without it. These results suggest that constitutive expression of HIF-1alpha contributes to the survival and proliferation of pancreatic cancer cells in hypoxia and glucose deprivation through the activation of anaerobic metabolism.
Akakura
N
N
Division of Cancer Pathobiology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
Kobayashi
M
M
Horiuchi
I
I
Suzuki
A
A
Wang
J
J
Chen
J
J
Niizeki
H
H
Kawamura Ki
Hosokawa
M
M
Asaka
M
M
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002455:Cell Division / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D005634:Fructose-Bisphosphate Aldolase / Q000096:biosynthesis / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D005947:Glucose / Q000172:deficiency*; D051272:Glucose Transporter Type 1; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051379:Mice; D008819:Mice, Nude; D009004:Monosaccharide Transport Proteins / Q000096:biosynthesis / Q000235:genetics; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D010100:Oxygen / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors; D014162:Transfection; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D051272:Glucose Transporter Type 1; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009004:Monosaccharide Transport Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; C495677:SLC2A1 protein, human; C495678:Slc2a1 protein, mouse; D014157:Transcription Factors; D005634:Fructose-Bisphosphate Aldolase; D005947:Glucose; D010100:Oxygen