Hereditary leiomyomatosis and renal cell carcinoma pathway (Homo sapiens)
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Description
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)
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Bibliography
- Linehan WM, Rouault TA; ''Molecular pathways: Fumarate hydratase-deficient kidney cancer--targeting the Warburg effect in cancer.''; Clin Cancer Res, 2013 PubMed Europe PMC Scholia
- 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 PubMed Europe PMC Scholia
- Schmidt L, Linehan W; ''Hereditary leiomyomatosis and renal cell carcinoma''; DovePress, 2014 PubMed Europe PMC Scholia
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