Dominant-negative hypoxia-inducible factor-1 alpha reduces tumorigenicity of pancreatic cancer cells through the suppression of glucose metabolism.
In the tumor cells exposed to hypoxia, hypoxia-inducible factor-1 (HIF-1)-mediated adaptation responses such as angiogenesis and anaerobic metabolism are induced for their survival. We have recently reported that the constitutive expression of HIF-1 alpha renders pancreatic cancer cells resistant to apoptosis induced by hypoxia and glucose deprivation. We then established dominant-negative HIF-1 alpha (dnHIF-1 alpha) transfectants and examined their susceptibility to apoptosis and growth inhibition induced by hypoxia and glucose deprivation in vitro and their tumorigenicity in SCID mice. We further examined the expressions of aldolase A and Glut-1 in vitro and Glut-1 expression and glucose uptake in the tumor tissues and microvessel counts in the tumor tissues. As a result, dnHIF-1 alpha rendered the pancreatic cancer cells sensitive to apoptosis and growth inhibition induced by hypoxia and glucose deprivation. Also it abrogated the enhanced expression of Glut-1 and aldolase A mRNAs under hypoxia and reduced the expression of Glut-1 and the glucose uptake in the tumor tissues and consequently in vivo tumorigenicity. We found no significant difference in the microvessel counts among the tumor tissues. From these results, we suggest that the disruption of the HIF-1 pathway might be effective in the treatment of pancreatic cancers.
Chen
Jian
J
Division of Cancer Pathobiology, Institute for Genetic Medicine, Hokkaido University, and Department of Surgical Oncology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Zhao
Songji
S
Nakada
Kunihiro
K
Kuge
Yuji
Y
Tamaki
Nagara
N
Okada
Futoshi
F
Wang
Jingxin
J
Shindo
Masanobu
M
Higashino
Fumihiro
F
Takeda
Kohji
K
Asaka
Masahiro
M
Katoh
Hiroyuki
H
Sugiyama
Toshio
T
Hosokawa
Masuo
M
Kobayashi
Masanobu
M
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D000818:Animals; D017209:Apoptosis; D001692:Biological Transport; D015152:Blotting, Northern; D002455:Cell Division; D003847:Deoxyglucose / Q000493:pharmacokinetics; D005434:Flow Cytometry; D005799:Genes, Dominant; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007700:Kinetics; D051379:Mice; D016513:Mice, SCID; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011994:Recombinant Proteins; D014157:Transcription Factors; D003847:Deoxyglucose; D005947:Glucose