Dataset Information

Molecular pathways: Fumarate hydratase-deficient kidney cancer--targeting the Warburg effect in cancer.

ABSTRACT: 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.

SUBMITTER: Linehan WM

PROVIDER: S-EPMC4447120 | biostudies-other | 2013 Jul

REPOSITORIES: biostudies-other

ACCESS DATA

Publications

Molecular pathways: Fumarate hydratase-deficient kidney cancer--targeting the Warburg effect in cancer.

Linehan W Marston WM Rouault Tracey A TA

Clinical cancer research : an official journal of the American Association for Cancer Research 20130430 13

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 meta ...[more]

PMID: 23633457

Similar Datasets

Project description:The role of energy deregulation and altered/adapted metabolism in tumor cells is an increasingly important issue in understanding cancer. Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an aggressive form of RCC characterized by germline mutation of fumarate hydratase (FH), followed by somatic loss of the remaining wild-type allele and known to be a highly metastatic and lethal malignancy compared to other RCCs. The intrinsic loss of normal tricarboxylic acid (TCA) cycle presumably aids tumorigenesis due to the necessary metabolic alterations required and the enforced dependence on glycolysis derived energy, mimicking the Warburg effect. Thus, there is considerable utility in establishing a preclinical cell model from these tumors to study energy metabolism deregulation, as well as developing new targeted therapeutic approaches for TCA cycle enzyme-deficient cancers. Here, we describe a new immortalized cell line, UOK268, derived from a patient's primary HLRCC-associated kidney cancer. This represents the first primary renal cell line to model TCA cycle gene loss and provides a perfect partner cell line to our previously described metastasis-derived HLRCC-associated cell line, UOK262. We identified a novel germline FH missense mutation, p.His192Asp, and the subsequent loss of heterozygosity in UOK268. The UOK268 cell line expressed mutant FH protein, which localized to the mitochondria, but with loss of almost all catalytic activity. The UOK268 cells had severely compromised oxidative phosphorylation and increased glycolytic flux. Ingenuity pathways analysis of human mitochondria-focused cDNA microarray (hMitChip3) gene chip data confirmed the altered mRNA expression patterns of genes involved in several important pathways, such as lipid metabolism, apoptosis, and energy production/glycolysis. UOK268 provides a unique model of a primary cell line demonstrating an enforced, irreversible Warburg effect and, combined with UOK262, provides a unique in vitro preclinical model for studying the bioenergetics of the Warburg effect in human cancer.

Dataset Information

Molecular pathways: Fumarate hydratase-deficient kidney cancer--targeting the Warburg effect in cancer.

Publications

Molecular pathways: Fumarate hydratase-deficient kidney cancer--targeting the Warburg effect in cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets