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Metabolic enzyme stops progression of most common type of kidney cancer
Date:7/20/2014

ed the Kreb's cycle, generate energy from carbohydrates, fats, and proteins in the form of ATP. However, the Kreb's cycle is hyperactive in ccRCC, resulting in enhanced lipid production. Renal cancer cells are associated with changes in two important intracellular proteins: elevated expression of hypoxia inducible factors (HIFs) and mutations in the von Hippel-Lindau (VHL) encoded protein, pVHL. In fact, mutations in pVHL occur in 90 percent of ccRCC tumors. pVHL regulates HIFs, which in turn affect activity of the Kreb's cycle.

Although much is already known about metabolic pathways and their role in cancer, there are still important questions to be answered. For example, kidney-specific VHL deletion in mice does not elicit clear cell-specific tumor formation, suggesting that additional mechanisms are at play. Toward answering that hunch, recent large-scale sequencing analyses have revealed the loss of several epigenetic enzymes in certain types of ccRCCs, suggesting that changes within the nucleus also account for kidney tumor progression.

To complement genetic studies revealing a role for epigenetic enzymes, the team evaluated metabolic enzymes in the 600-plus tumors they analyzed. The expression of FBP1 was lost in all kidney cancer tissue samples examined. They found FBP1 protein in the cytoplasm of normal cells, where it would be expected to be active in glucose metabolism. But, they also found FBP1 in the nucleus of these normal cells, where it binds to HIF to modulate its effects on tumor growth. In cells without FBPI, the team observed the Warburg effect a phenomenon in which malignant, rapidly growing tumor cells go into overdrive, producing energy up to 200 times faster than their non-cancer-cell counterparts.

This unique dual function of FBP1 explains its ubiquitous loss in ccRCC, distinguishing FBP1 from previously identified tumor suppressors that are not consistently inhibited in all tumors. "And since FBP1 activity is al
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Contact: Karen Kreeger
karen.kreeger@uphs.upenn.edu
215-349-5658
University of Pennsylvania School of Medicine
Source:Eurekalert  

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