Hypoxia upregulates the gene expression of mitochondrial aconitase in prostate carcinoma cells.

Abstract

Hypoxia induces metabolic alteration in cancer cells by stabilizing hypoxia-inducible factor 1α (HIF-1α (HIF1A)), which regulates the bioenergetic genes of glycolysis and lipid metabolic pathways. However, the target genes of hypoxia-induced metabolic alterations in the prostate remain uncertain. Mitochondrial aconitase (mACON) (ACONM) is an enzyme that is central to carbohydrate and energy metabolism and is responsible for the interconversion of citrate to isocitrate as part of the citric acid cycle in the human prostate. We evaluated the effects of the molecular mechanisms of hypoxia on mACON gene expression in PC-3 and LNCaP human prostate carcinoma cells. Immunoblotting assays revealed that hypoxia modulated mACON and lactate dehydrogenase A (LDHA) protein expression, while these effects were attenuated when HIF-1α was knocked down. Hypoxia induced fatty acid synthase (FASN) in PC-3 cells while hypoxia blocked FASN gene expression in LNCaP cells after 24-h incubation. Results of real-time RT-qPCR, immunoblotting, and transient gene expression assays revealed that hypoxia treatment or co-transfection with HIF-1α expression vector enhanced gene expression of mACON, implying that hypoxia modulated mACON at the transcriptional level. Hypoxia-induced mACON promoter activity is dependent on the DNA fragment located at -1013 to -842 upstream of the translation initiation site. l-mimosine, an iron chelator, stabilized HIF-1α but downregulated mACON gene expression, suggesting that iron chelation blocked the hypoxia-induced mACON gene expression. These results suggest that hypoxia dysregulates the expressions of LDHA, FASN, and mACON genes, and the hypoxia-induced mACON gene expression is via the HIF-1α-dependent and iron-dependent pathways in prostate carcinoma cells.

• Authors: Ke-Hung Tsui, Li-Chuan Chung, Shyi-Wu Wang, Tsui-Hsia Feng, Phei-Lang Chang, Horng-Heng Juang
• Journal: Journal of molecular endocrinology (J Mol Endocrinol) Vol. 51 Issue 1 Pg. 131-41 ( 2013) ISSN: 1479-6813 [Electronic] England
• PMID: 23709747 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Hypoxia-Inducible Factor 1, alpha Subunit
• Aconitate Hydratase

Topics

• Aconitate Hydratase (genetics, metabolism)
• Carcinoma (genetics, metabolism)
• Cell Hypoxia
• Cell Line, Tumor
• Gene Expression Regulation, Neoplastic
• Gene Knockdown Techniques
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Male
• Mitochondria (genetics, metabolism)
• Prostatic Neoplasms (genetics, metabolism)