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Metabolic Enzyme Stops Growth of Most Common Type of Kidney Cancer

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Key Points

  • Investigators evaluated metabolic enzymes in the over 600 tumors and found that expression of FBP1 was lost in all kidney cancer tissue samples examined.
  • In normal cells, FBP1 was found in both the cytoplasm, where it would be expected to be active in glucose metabolism, and the nucleus, where it bound to HIF to modulate its effects on tumor growth.

In an analysis of metabolites in human kidney tissue, a research team from the Perelman School of Medicine at the University of Pennsylvania identified an enzyme key to applying the brakes on tumor growth. The new study, published in Nature by Simon et al, demonstrated that an enzyme called FBP1, which is essential for regulating metabolism, binds to a transcription factor in the nucleus of certain kidney cells and restrains energy production in the cell body.

The researchers determined that this enzyme is missing from all kidney tumor tissue analyzed. When FBP1 is working properly, out-of-control cell growth is kept in check, but without the enzyme, tumor cells produce energy at a much faster rate than their noncancer cell counterparts.

A Personalized Approach for Kidney Cancer?

Clear cell renal cell carcinoma, the most frequent form of kidney cancer, is characterized by elevated glycogen and fat deposits in affected kidney cells. In the past decade, clear cell renal cell carcinomas have been on the rise worldwide. However, if tumors are removed early, a patient’s prognosis for 5-year survival is relatively good. If expression of the FBP1 gene is lost, patients have a worse prognosis.

“This study is the first stop in this line of research for coming up with a personalized approach for people with clear cell renal cell carcinoma–related mutations,” said Celeste Simon, PhD, Professor of Cell and Developmental Biology, Scientific Director for the Abramson Family Cancer Research Institute, and investigator with the Howard Hughes Medical Institute.

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% of clear cell renal cell carcinoma tumors. pVHL regulates HIFs, which in turn affect activity of the Kreb’s cycle.

Study Details

Recent large-scale sequencing analyses have revealed the loss of several epigenetic enzymes in certain types of clear cell renal cell carcinomas, suggesting that changes within the nucleus also account for kidney tumor progression.

To complement genetic studies revealing a role for epigenetic enzymes, the investigators 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 clear cell renal cell carcinoma, distinguishing FBP1 from previously identified tumor suppressors that are not consistently inhibited in all tumors. “And since FBP1 activity is also lost in liver cancer, which is quite prevalent, FBP1 depletion may be generally applicable to a number of human cancers,” noted Dr. Simon.

According to the researchers, the next steps will be to identify other metabolic pathways to target, measure the abundance of metabolites in kidney and liver cancer cells to determine FBP1’s role in each, and develop a better mouse model for preclinical studies.

Dr. Simon is the corresponding author for the Nature article.

This work was supported by the Howard Hughes Medical Institute, and the National Cancer Institute.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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