Enzyme may halt tumor growth in kidney cancer

Date: Jul-22-2014 Researchers in the US have discovered an enzyme called FBP1 - already known to be important

for controlling metabolism in cells - plays a surprising role in switching genes on and off

in kidney cancer. They suggest the enzyme may be key to halting tumor growth in clear cell renal

cell carcinoma, the most common kidney cancer.

The team, from the University of Pennsylvania (Penn), also found the enzyme, which is

present in normal cells, was missing from tumor cells in all of the 600 tumors they

analyzed.

The researchers came across the enzyme while analyzing

metabolites - small molecules used to make fuel - in normal and cancerous human kidney

tissue.

FBP1 stops cells growing out of control

FBP1 - short for Fructose-1,6-bisphosphatase - is essential for regulating metabolism, they

note in their Nature paper. The enzyme binds to a transcription factor - a molecule that

controls gene activity - in the nucleus of certain kidney cells and restrains cellular energy

production.

The researchers found that FBP1 plays a surprising role in switching genes on and off

in cancer of the kidneys.

A feature of clear cell renal cell carcinoma (ccRCC) is higher levels of the carbohydrate

glycogen and deposits of fat in affected kidney cells. The fat deposits accumulate as clear

droplets, giving the cancer its name.

Rates of the cancer have been rising worldwide over the last 10 years. Patients have a good

chance of survival if tumors are removed early. Their prognosis is not so good however, if the

FBP1 gene is turned off.

For their study, the researchers analyzed tissue samples from over 600 ccRCC tumors and found

none of them contained the enzyme. They also found that without the enzyme, the tumor cells

produced energy at a much faster rate than normal cells. They deduced that FBP1 stops cells

growing out of control.

Study leader Celeste Simon, a professor of Cell and Developmental Biology and the scientific

director for Penn's Abramson Family Cancer Research Institute at Penn, says their 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."

FBP1 was switched off in all the 600-plus tumor samples examined

In their paper, the team explains how in ccRCC a series of faulty biochemical reactions called

the Kreb's cycle result in over-production of lipids, and how this is linked to mutations in

certain genes that affect two types of protein called HIFs and pVHL - mutations in pVHL occur in

90% of ccRCC tumors.

Although much is known about metabolic pathways and their role in cancer, they note, there are

still areas that are unclear. Recent large-scale gene sequencing studies have revealed absence of

certain enzymes in some types of ccRCCs, suggesting perhaps changes in the nucleus may also

contribute to tumor progression.

To investigate this further, the team evaluated epigenetic enzymes - molecules that influence

genes without actually changing them - in over 600 tumors. They found FBP1 was switched off

(expression was lost) in all the samples they examined.

However, they found FBP1 was present in the cytoplasm - the fluid inside the cell - of normal

cells. This was where they expected to find it, since it is where it would be active in the

control of glucose metabolism.

But unexpectedly, they also found FBP1 in the nucleus of normal cells where it seems to play a

different role - it binds to HIF protein to influence its effect on tumor growth.

In cells lacking FBP1, the team observed a phenomenon known as the Warburg effect - where

malignant cells go into overdrive, producing energy 200 times faster than normal cells to fuel

rapid tumor growth.

Finding may also be important for liver and other cancers

This dual role of FBP1 distinguishes it from other tumor suppressors that are not consistently

inhibited in all tumors. The team believes the finding may be important for other cancers too,

as Prof. Simon notes:

"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."

The researchers say what is now needed is a better mouse model for preclinical studies and to

find other metabolic pathways to target. Also useful will be to clarify FBP1's role in liver and

cancer cells by further assessing levels of metabolites.

Funds from the Howard Hughes Medical Institute and the National Cancer Institute helped

support the study.

Meanwhile, Medical News Today recently learned how low cholesterol is not a good sign for

kidney cancer patients. An analysis led by the Medical University of Vienna, Austria, found

kidney cancer patients who had low blood cholesterol before treatment tended to develop more

advanced tumors and patients with high levels of cholesterol had a 43% lower risk of dying from

their kidney cancer.

Written by Catharine Paddock PhD

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Courtesy: Medical News Today Note: Any medical information available in this news section is not intended as a substitute for informed medical advice and you should not take any action before consulting with a health care professional.