Hereditary leiomyomatosis and renal cell carcinoma pathway (WP4206)

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an autosomal dominant hereditary cancer syndrome in which affected individuals are at risk for the development of cutaneous and uterine leiomyomas and kidney cancer. HLRCC is characterized by germline mutation of the tricarboxylic acid cycle (TCA) enzyme, fumarate hydratase (FH). FH-deficient kidney cancer is characterized by impaired oxidative phosphorylation and a metabolic shift to aerobic glycolysis, a form of metabolic reprogramming referred to as the Warburg effect. AMPK is a negative regulator of the Warburg effect in Fumarate hydratase-deficient kidney cancer. Fumarate hydratase (FH)-deficient kidney cancer, characterized by impaired oxidative phosphorylation, and undergoes a metabolic shift to aerobic glycolysis to generate ATP required for the increased energetic demands of rapidly proliferating cells. The increased glycolysis suppresses expression and activation of AMPK which results in increased S6 and ACC activity, promoting anabolic growth and proliferation. Decreased AMPK results in decreased p53 and the iron transporter, DMT1. The iron responsive proteins, IRP1 and IRP2, as well as the IRP target, transferrin receptor protein 1 (TFRC) are elevated, indicating that cytosolic iron concentrations decrease secondary to decreased DMT1 activity. Prolyl hydroxylase, which is sensitive to iron levels, would be inhibited by decreased cytosolic iron levels, stabilizing HIF1α. Fumarate, which increases in FH- deficient cells, has been shown to inhibit prolyl hydroxylase, which would lead to further stabilization of HIF1α, increasing transcription of factors such as vascular endothelial growth factor (VEGF) and the glucose transporter, GLUT1. Increased fumarate has been shown to succinate KEAP1, thus altering it's conformation and disrupting its ability to induce degradation of Nrf2. Nrf2 transcription is increased activating anti-oxidant response and protecting against oxidative stress. Increased HIF1α would stimulate LDHA, increasing lactate production, and would stimulate PDK1, which inhibits PDH and would decrease entry of pyruvate into the TCA cycle. FH-deficient kidney cancer use a glutamine- dependent reductive carboxylation rather than rather than oxidative metabolism for citrate formation (red arrows). Glutamine is the major source for the increased fatty acid synthesis required for rapid proliferation in these cells with disabled normal oxidative phosphorylation. Potential approaches for treatment of this aggressive form of kidney cancer include agents that stimulate AMPK, agents that target the tumor vasculature and glucose transport, agents that inhibit LDHA and agents that target the critical glutamine-dependent reductive fatty acid/lipid synthetic pathway. (Linehan and Rouault, Clin Cancer Res, 2013)
last edited

Authors

Kristina Hanspers , Egon Willighagen , Maintenance bot , Friederike Ehrhart , and Finterly Hu

Cited In

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Organism

Homo sapiens

Communities

CPTAC Diseases Renal Genomics Pathways

Annotations

Pathway Ontology: renal cell carcinoma pathway cancer pathway

Disease Ontology: leiomyomatosis renal cell carcinoma

Participants

Label Type Compact Identifier
phospholipids Metabolite chebi:16247
ATP Metabolite chebi:15422
glucose Metabolite chebi:17234
lactate Metabolite chebi:24996
O2+ Metabolite chebi:29371
iron Metabolite chebi:18248
Iron Metabolite hmdb:HMDB0015531
FH Metabolite chebi:73634
CO2 Metabolite chebi:16526
pyruvate Metabolite chebi:15361
glucose Metabolite chebi:17234
pyruvate Metabolite chebi:15361
Acetyl-CoA Metabolite hmdb:HMDB0001206
fatty acids Metabolite chebi:35366
malonyl-CoA Metabolite chebi:57384
citrate Metabolite chebi:16947
Acetyl-CoA Metabolite hmdb:HMDB0001206
L-malate Metabolite chebi:15589
Oxaloacetate Metabolite chebi:30744
citrate Metabolite chebi:16947
isocitrate Metabolite chebi:16087
alpha-ketoglutarate Metabolite chebi:16810
Succinyl-CoA Metabolite hmdb:HMDB0001022
succinate Metabolite chebi:30031
fumarate Metabolite chebi:29806
L-malate Metabolite chebi:15589
Oxaloacetate Metabolite chebi:30744
alpha-ketoglutarate Metabolite chebi:16810
glutamate Metabolite chebi:14321
glutamate Metabolite chebi:14321
alpha-ketoglutarate Metabolite chebi:16810
succinate Metabolite chebi:30031
TP53 GeneProduct ensembl:ENSG00000141510
PDK1 GeneProduct ensembl:ENSG00000152256
PRKAB1 GeneProduct ensembl:ENSG00000111725
EGLN1 GeneProduct ensembl:ENSG00000135766
NFE2L2 GeneProduct ensembl:ENSG00000116044
PDHA1 GeneProduct ensembl:ENSG00000131828
LDHA GeneProduct ensembl:ENSG00000134333
PRKAA1 GeneProduct ensembl:ENSG00000132356
PRKAG1 GeneProduct ensembl:ENSG00000181929
SLC11A2 GeneProduct ensembl:ENSG00000110911
RPS6 GeneProduct ensembl:ENSG00000137154
ACACA GeneProduct ensembl:ENSG00000278540
ACACB GeneProduct ensembl:ENSG00000076555
PRKAB1 GeneProduct ensembl:ENSG00000111725
PRKAA1 GeneProduct ensembl:ENSG00000132356
PRKAG1 GeneProduct ensembl:ENSG00000181929
PDHA2 GeneProduct ensembl:ENSG00000163114
PDHB GeneProduct ensembl:ENSG00000168291
NFE2L2 GeneProduct ensembl:ENSG00000116044
KEAP1 GeneProduct ensembl:ENSG00000079999
KEAP1 GeneProduct ensembl:ENSG00000079999
CUL3 GeneProduct ensembl:ENSG00000036257
HIF1A GeneProduct ensembl:ENSG00000100644
GLUT1 GeneProduct ensembl:ENSG00000117394
VEGFA GeneProduct ensembl:ENSG00000112715

References

  1. Linehan WM, Rouault TA. Molecular pathways: Fumarate hydratase-deficient kidney cancer--targeting the Warburg effect in cancer. Clin Cancer Res. 2013 Jul 1;19(13):3345–52. PubMed Europe PMC Scholia
  2. Schmidt LS, Linehan WM. Hereditary leiomyomatosis and renal cell carcinoma. Int J Nephrol Renovasc Dis. 2014 Jun 20;7:253–60. PubMed Europe PMC Scholia
  3. Srinivasan R, Ricketts CJ, Sourbier C, Linehan WM. New strategies in renal cell carcinoma: targeting the genetic and metabolic basis of disease. Clin Cancer Res. 2015 Jan 1;21(1):10–7. PubMed Europe PMC Scholia