Regulation of phosphoglucose isomerase/autocrine motility factor expression by hypoxia.

Abstract

Phosphoglucose isomerase (PGI; EC 5.3.1.9) is a housekeeping cytosolic enzyme of the sugar metabolism pathways that plays a key role in glycolysis and gluconeogenesis. PGI is a multifunctional dimeric protein that extracellularly acts as a cytokine with properties that include autocrine motility factor (AMF) eliciting mitogenic, motogenic, differentiation functions and has been implicated in tumor progression and metastasis. Since metastasis is regulated in part by hypoxia, which induces the transcription of metastasis-associated genes and anaerobic glycolic metabolism, we questioned whether hypoxia also regulates the expression level of tumor cells' PGI/AMF. We establish here that in the human breast carcinoma BT-549 cells hypoxia enhanced expression of the transcription factor hypoxia-inducible factor (HIF)-1, which in turn led to the up-regulation of PGI/AMF expression and was specifically inhibited by inhibitors of the phosphatidylinositol 3'-kinase signaling pathway. In addition, the hypoxia induction of PGI/AMF expression was suppressed by inhibitors of vascular endothelial growth factor (VEGF) or VEGF receptors, suggesting that hypoxia-inducible VEGF regulates the PGI/AMF expression. Hypoxia also enhanced cancer cell motility, and these effects were strongly inhibited by the PGI/AMF, VEGF, or VEGF receptor inhibitors. The results presented here suggest that under hypoxic conditions the expression of PGI/AMF is regulated in part by the HIF pathway, which in turn increases the flow of the glycolytic cascade leading to an increased anaerobic energy generation; thus, inhibition of PGI/AMF expression and activities may provide a new therapeutic modality for treatment of hypoxic tumors.

• Authors: Tatsuyoshi Funasaka, Takashi Yanagawa, Victor Hogan, Avraham Raz
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 19 Issue 11 Pg. 1422-30 (Sep 2005) ISSN: 1530-6860 [Electronic] United States
• PMID: 16126909 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Indazoles
• Vascular Endothelial Growth Factor A
• 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole
• Phosphatidylinositol 3-Kinases
• Glucose-6-Phosphate Isomerase

Topics

• Cell Line, Tumor
• Cell Movement
• Gene Expression Regulation, Neoplastic
• Glucose-6-Phosphate Isomerase (genetics)
• Humans
• Hypoxia (metabolism)
• Hypoxia-Inducible Factor 1, alpha Subunit (physiology)
• Indazoles (pharmacology)
• Phosphatidylinositol 3-Kinases (physiology)
• Signal Transduction
• Vascular Endothelial Growth Factor A (biosynthesis)