HIF-1α activation under glucose deprivation plays a central role in the acquisition of anti-apoptosis in human colon cancer cells

Nishimoto,Arata; Kugimiya,Naruji; Hosoyama,Tohru; Enoki,Tadahiko; Li,Tao-Sheng; Hamano,Kimikazu

doi:10.3892/ijo.2014.2367

HIF-1α activation under glucose deprivation plays a central role in the acquisition of anti-apoptosis in human colon cancer cells

Authors:
- Arata Nishimoto
- Naruji Kugimiya
- Tohru Hosoyama
- Tadahiko Enoki
- Tao-Sheng Li
- Kimikazu Hamano
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Affiliations: Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan, Department of Stem Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan
Published online on: April 3, 2014 https://doi.org/10.3892/ijo.2014.2367
Pages: 2077-2084

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Abstract

A poor vascular network development in a tumor mass leads to poor oxygen and nutrient supply. To adapt to a hypoxic microenvironment, it is well-known that cancer cells activate the transcription factor hypoxia-inducible factor-1α (HIF-1α). HIF-1α plays a central role in hypoxia-induced metabolic switching, anti-apoptosis, angiogenesis and drug resistance. Glucose deprivation, another major stressful microenvironment, protects cancer cells from drug-induced apoptosis. However, the molecular mechanisms by which cancer cells adapt to poor nutrient conditions remain poorly understood. In this study, we focused on HIF-1α, signal transducer and activator of transcription 3 (STAT3) and transcription factor 4 (TCF4), which are involved in cell survival, anti-apoptosis and drug resistance. We examined their activities and the relationships among these transcription factors under glucose deprivation. Our results showed that glucose deprivation increased HIF-1α, STAT3 and TCF4 DNA-binding activity, as well as the expression levels of their target genes OCT4, BCL-2 and VEGF. HIF-1α knockdown significantly increased poly(ADP-ribose) polymerase 1 (PARP-1) cleavage at higher levels than STAT3 knockdown under glucose deprivation. Furthermore, HIF-1α knockdown led to a significant decrease in the expression levels of both STAT3 and TCF4, although STAT3 knockdown decreased only HIF-1α expression level. Our data indicated that activation of the HIF-1α signaling pathway under glucose deprivation leads to the acquisition of anti-apoptotic properties in human colon cancer cells, and targeting the HIF-1α signaling pathway may provide an effective avenue for treating cancers resistant to conventional therapy.

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