HIF-1α activation under glucose deprivation plays a central role in the acquisition of anti-apoptosis in human colon cancer cells.
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 trans-cription 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.
Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan.
Arata
A
Nishimoto
Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan.
Naruji
N
Kugimiya
Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan.
Tohru
T
Hosoyama
Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan.
Tadahiko
T
Enoki
Department of Stem Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan.
Tao-Sheng
TS
Li
Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan.
Kimikazu
K
Hamano
D017209:Apoptosis; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D005947:Glucose