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The glycolytic shift in fumarate-hydratase-deficient kidney cancer lowers AMPK levels, increases anabolic propensities and lowers cellular iron levels.

ABSTRACT: Inactivation of the TCA cycle enzyme, fumarate hydratase (FH), drives a metabolic shift to aerobic glycolysis in FH-deficient kidney tumors and cell lines from patients with hereditary leiomyomatosis renal cell cancer (HLRCC), resulting in decreased levels of AMP-activated kinase (AMPK) and p53 tumor suppressor, and activation of the anabolic factors, acetyl-CoA carboxylase and ribosomal protein S6. Reduced AMPK levels lead to diminished expression of the DMT1 iron transporter, and the resulting cytosolic iron deficiency activates the iron regulatory proteins, IRP1 and IRP2, and increases expression of the hypoxia inducible factor HIF-1?, but not HIF-2?. Silencing of HIF-1? or activation of AMPK diminishes invasive activities, indicating that alterations of HIF-1? and AMPK contribute to the oncogenic growth of FH-deficient cells.

SUBMITTER: Tong WH

PROVIDER: S-EPMC3174047 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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The glycolytic shift in fumarate-hydratase-deficient kidney cancer lowers AMPK levels, increases anabolic propensities and lowers cellular iron levels.

Tong Wing-Hang WH Sourbier Carole C Kovtunovych Gennady G Jeong Suh Young SY Vira Manish M Ghosh Manik M Romero Vladimir Valera VV Sougrat Rachid R Vaulont Sophie S Viollet Benoit B Kim Yeong-Sang YS Lee Sunmin S Trepel Jane J Srinivasan Ramaprasad R Bratslavsky Gennady G Yang Youfeng Y Linehan W Marston WM Rouault Tracey A TA

Cancer cell 20110901 3

Inactivation of the TCA cycle enzyme, fumarate hydratase (FH), drives a metabolic shift to aerobic glycolysis in FH-deficient kidney tumors and cell lines from patients with hereditary leiomyomatosis renal cell cancer (HLRCC), resulting in decreased levels of AMP-activated kinase (AMPK) and p53 tumor suppressor, and activation of the anabolic factors, acetyl-CoA carboxylase and ribosomal protein S6. Reduced AMPK levels lead to diminished expression of the DMT1 iron transporter, and the resulting ...[more]

PMID: 21907923

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Project description:Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a hereditary cancer syndrome in which affected individuals are at risk for development of cutaneous and uterine leiomyomas and an aggressive form of type II papillary kidney cancer. HLRCC is characterized by germline mutation of the tricarboxylic acid (TCA) cycle 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. Increased glycolysis generates ATP needed for increased cell proliferation. In FH-deficient kidney cancer, levels of AMP-activated protein kinase (AMPK), a cellular energy sensor, are decreased resulting in diminished p53 levels, decreased expression of the iron importer, DMT1, leading to low cellular iron levels, and to enhanced fatty acid synthesis by diminishing phosphorylation of acetyl CoA carboxylase, a rate-limiting step for fatty acid synthesis. Increased fumarate and decreased iron levels in FH-deficient kidney cancer cells inactivate prolyl hydroxylases, leading to stabilization of hypoxia-inducible factor (HIF)-1? and increased expression of genes such as VEGF and glucose transporter 1 (GLUT1) to provide fuel needed for rapid growth demands. Several therapeutic approaches for targeting the metabolic basis of FH-deficient kidney cancer are under development or are being evaluated in clinical trials, including the use of agents such as metformin, which would reverse the inactivation of AMPK, approaches to inhibit glucose transport, lactate dehydrogenase A (LDHA), the antioxidant response pathway, the heme oxygenase pathway, and approaches to target the tumor vasculature and glucose transport with agents such as bevacizumab and erlotinib. These same types of metabolic shifts, to aerobic glycolysis with decreased oxidative phosphorylation, have been found in a wide variety of other cancer types. Targeting the metabolic basis of a rare cancer such as FH-deficient kidney cancer will hopefully provide insights into the development of effective forms of therapies for other, more common forms of cancer.

Dataset Information

The glycolytic shift in fumarate-hydratase-deficient kidney cancer lowers AMPK levels, increases anabolic propensities and lowers cellular iron levels.

Publications

The glycolytic shift in fumarate-hydratase-deficient kidney cancer lowers AMPK levels, increases anabolic propensities and lowers cellular iron levels.

Similar Datasets

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