TY - JOUR
T1 - Expression profiling in progressive stages of fumarate-hydratase deficiency
T2 - the contribution of metabolic changes to tumorigenesis
AU - Ashrafian, Houman
AU - O'Flaherty, Linda
AU - Adam, Julie
AU - Steeples, Violetta
AU - Chung, Yuen-Li
AU - East, Phil
AU - Vanharanta, Sakari
AU - Lehtonen, Heli
AU - Nye, Emma
AU - Hatipoglu, Emine
AU - Miranda, Melroy
AU - Howarth, Kimberley
AU - Shukla, Deepa
AU - Troy, Helen
AU - Griffiths, John
AU - Spencer-Dene, Bradley
AU - Yusuf, Mohammed
AU - Volpi, Emanuela
AU - Maxwell, Patrick H
AU - Stamp, Gordon
AU - Poulsom, Richard
AU - Pugh, Christopher W
AU - Costa, Barbara
AU - Bardella, Chiara
AU - Di Renzo, Maria Flavia
AU - Kotlikoff, Michael I
AU - Launonen, Virpi
AU - Aaltonen, Lauri
AU - El-Bahrawy, Mona
AU - Tomlinson, Ian
AU - Pollard, Patrick J
N1 - Copyright © 2010 AACR.
PY - 2010/11/15
Y1 - 2010/11/15
N2 - 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.
AB - 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.
KW - Animals
KW - Carcinoma, Renal Cell/genetics
KW - Cell Proliferation
KW - Cells, Cultured
KW - Embryo, Mammalian/cytology
KW - Female
KW - Fibroblasts/cytology
KW - Fumarate Hydratase/deficiency
KW - Gene Expression Profiling
KW - Gene Expression Regulation, Enzymologic
KW - Glycolysis
KW - Humans
KW - Hypoxia-Inducible Factor 1, alpha Subunit/genetics
KW - Kidney Neoplasms/genetics
KW - Leiomyomatosis/genetics
KW - Male
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - Muscle, Smooth/metabolism
KW - Neoplasms/genetics
KW - Oligonucleotide Array Sequence Analysis
KW - Reverse Transcriptase Polymerase Chain Reaction
KW - Spectral Karyotyping
U2 - 10.1158/0008-5472.CAN-10-1949
DO - 10.1158/0008-5472.CAN-10-1949
M3 - Article
C2 - 20978192
SN - 0008-5472
VL - 70
SP - 9153
EP - 9165
JO - Cancer Research
JF - Cancer Research
IS - 22
ER -