GRIM-19 opposes reprogramming of glioblastoma cell metabolism via HIF1α destabilization.

Abstract

The metabolism that sustains cancer cells is adapted preferentially to glycolysis, even under aerobic conditions (Warburg effect). This effect was one of the first alterations in cancer cells recognized as conferring a survival advantage. In this study, we show that gene associated with retinoid-interferon-induced mortality-19 (GRIM-19), which was previously identified as a tumor suppressor protein associated with growth inhibition and cell apoptosis, contributes to the switch between oxidative and glycolytic pathways. In parallel to this, vascular endothelial growth factor, which promotes neovascularization, is also regulated. We have identified hypoxia-inducible factor 1α (HIF1α) as the downstream factor of GRIM-19 in human glioblastoma cell lines. Downregulation of GRIM-19 promotes HIF1α synthesis in a STAT3-dependent manner, which acts as a potential competitive inhibitor for von Hippel-Lindau (pVHL)-HIF1α interaction, and thereby prevents HIF1α from pVHL-mediated ubiquitination and proteasomal degradation. Taken together, it is concluded that GRIM-19, a potential tumor suppressor gene, performs its function in part via regulating glioblastoma metabolic reprogramming through STAT3-HIF1α signaling axis, and this has added new perspective to its role in tumorigenesis, thus providing potential strategies for tumor metabolic therapy.

• Authors: Qian Liu, Lulu Wang, Zhaojuan Wang, Yang Yang, Jingxia Tian, Guoliang Liu, Dongshi Guan, Xinmin Cao, Yanmin Zhang, Aijun Hao
• Journal: Carcinogenesis (Carcinogenesis) Vol. 34 Issue 8 Pg. 1728-36 (Aug 2013) ISSN: 1460-2180 [Electronic] England
• PMID: 23580587 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apoptosis Regulatory Proteins
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• STAT3 Transcription Factor
• STAT3 protein, human
• Tumor Suppressor Proteins
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• NADH, NADPH Oxidoreductases
• NDUFA13 protein, human
• Proteasome Endopeptidase Complex

Topics

• Animals
• Apoptosis Regulatory Proteins (genetics, metabolism)
• Carcinogenesis (genetics, metabolism)
• Cell Growth Processes (genetics)
• Cell Line, Tumor
• Cell Respiration (genetics)
• Down-Regulation
• Endothelial Cells (metabolism)
• Glioblastoma (genetics, metabolism)
• Glycolysis (genetics)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Mice
• Mice, Inbred BALB C
• NADH, NADPH Oxidoreductases (genetics, metabolism)
• Proteasome Endopeptidase Complex (genetics, metabolism)
• Proteolysis
• STAT3 Transcription Factor (genetics, metabolism)
• Tumor Suppressor Proteins (genetics, metabolism)
• Ubiquitination (genetics)
• Vascular Endothelial Growth Factor A (genetics, metabolism)