Dominant-Negative Hypoxia-Inducible Factor-1α Reduces Tumorigenicity of Pancreatic Cancer Cells through the Suppression of Glucose Metabolism

Abstract

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.

Antiapoptotic action of hypoxia-inducible factor-1α in human endothelial cells

“…35 In this respect, it is worth noting that HIF-1a can mediate crosstalk between hypoxia and glucose metabolism via glucose response elements. 36,37 Since a significant proportion of transfected HUVECs did not manifest evidence of apoptotic changes by TUNEL assay and activated caspase-3 immunostaining after A/R in the current study, it is probable that other antiapoptotic proteins distinct from HIF-1a may also have conferred some cytoprotection against anoxic stress, as has been shown with respect to CD105 38 and Mcl-1. 39 In summary, we have employed RNAi targeting the HIF-1a gene in primary cultured HUVECs and have demonstrated the role of HIF-1a as an antiapoptotic protein in a model of anoxic stress.…”

Up-Regulation of Krüppel-Like Factor 5 in Pancreatic Cancer Is Promoted by Interleukin-1β Signaling and Hypoxia-Inducible Factor-1α

“…In favor of this hypothesis are results from a recently published study demonstrating that KRAS activation promotes KLF5 up-regulation in human colon cancer (HCT116) cells (13). Moreover, because hypoxia-mediated and cytokine-mediated activation of the oncogenic transcription factor hypoxia-inducible factor-1α (HIF-1α) is frequently encountered in pancreatic tumors, we also hypothesized that the interleukin (IL)-1β system and/or HIF-1α may be involved in the regulation of KLF5 expression (14)(15)(16)(17)(18). We therefore sought to further define the expression and regulation of KLF5 in human pancreatic cancer cells to expand our knowledge on this particular transcription factor and to potentially reveal a novel molecular therapeutic target.…”

Adipose Tissue-specific Inhibition of Hypoxia-inducible Factor 1α Induces Obesity and Glucose Intolerance by Impeding Energy Expenditure in Mice*

“…A deletion mutant of human HIF1␣ lacking the DNA-binding domain has previously been shown to act in a dn manner by suppressing the dimerization between functional HIF1␣ and HIF1␤ (29). In order to achieve the selective suppression of HIF1␣ in adipose tissue, we generated transgenic mice that overexpress a dn version of human HIF1␣ under the transcriptional control of a 5.4-kb aP2 (adipocyte fatty acidbinding protein) promoter, which has been widely used to drive transgene expression in adipose tissue (Fig.…”