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Expression Profiling in Progressive Stages of Fumarate-Hydratase Deficiency: The Contribution of Metabolic Changes to Tumorigenesis
- Publication Year :
- 2010
-
Abstract
- Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is caused by mutations in the Krebs cycle enzyme fumarate hydratase (FH). It has been proposed that “pseudohypoxic” stabilization of hypoxia-inducible factor-α (HIF-α) by fumarate accumulation contributes to tumorigenesis in HLRCC. We hypothesized that an additional direct consequence of FH deficiency is the establishment of a biosynthetic milieu. To investigate this hypothesis, we isolated primary mouse embryonic fibroblast (MEF) lines from Fh1-deficient mice. As predicted, these MEFs upregulated Hif-1α and HIF target genes directly as a result of FH deficiency. In addition, detailed metabolic assessment of these MEFs confirmed their dependence on glycolysis, and an elevated rate of lactate efflux, associated with the upregulation of glycolytic enzymes known to be associated with tumorigenesis. Correspondingly, Fh1-deficient benign murine renal cysts and an advanced human HLRCC-related renal cell carcinoma manifested a prominent and progressive increase in the expression of HIF-α target genes and in genes known to be relevant to tumorigenesis and metastasis. In accord with our hypothesis, in a variety of different FH-deficient tissues, including a novel murine model of Fh1-deficient smooth muscle, we show a striking and progressive upregulation of a tumorigenic metabolic profile, as manifested by increased PKM2 and LDHA protein. Based on the models assessed herein, we infer that that FH deficiency compels cells to adopt an early, reversible, and progressive protumorigenic metabolic milieu that is reminiscent of that driving the Warburg effect. Targets identified in these novel and diverse FH-deficient models represent excellent potential candidates for further mechanistic investigation and therapeutic metabolic manipulation in tumors. Cancer Res; 70(22); 9153–65. ©2010 AACR.
- Subjects :
- Male
Cancer Research
Biology
PKM2
medicine.disease_cause
Gene Expression Regulation, Enzymologic
Fumarate Hydratase
Mice
03 medical and health sciences
0302 clinical medicine
Downregulation and upregulation
Leiomyomatosis
Neoplasms
medicine
Animals
Humans
Glycolysis
Carcinoma, Renal Cell
Cells, Cultured
Cell Proliferation
Oligonucleotide Array Sequence Analysis
030304 developmental biology
Mice, Knockout
0303 health sciences
Reverse Transcriptase Polymerase Chain Reaction
Cell growth
Gene Expression Profiling
Spectral Karyotyping
Muscle, Smooth
Fibroblasts
Embryo, Mammalian
Hypoxia-Inducible Factor 1, alpha Subunit
Warburg effect
Kidney Neoplasms
3. Good health
Mice, Inbred C57BL
Oncology
Biochemistry
030220 oncology & carcinogenesis
Fumarase
Cancer research
Female
Hereditary leiomyomatosis and renal cell carcinoma
Carcinogenesis
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....8cbcbcf0d49726263f9c3c92b5ed56c4