Johns Hopkins Gazette: July 24, 1995

Blocking Off Cancer Cells' 'Sweet Tooth'

Michael Purdy
JHMI Office of Public Affairs

     "If we could knock out both of those energy-producing
processes, that would be a real killer.  There's no way a cancer
cell could survive that."

     Hopkins researchers have isolated a gene that helps many
cancer cells grow and reproduce at rapid rates, and have
determined the sequence of DNA building blocks that make up a
crucial part of that gene.

     The part, known as the regulatory region of the gene,
directs production of the first link in a chain of chemical
reactions that helps fuel runaway cell growth and reproduction.
If doctors can find a way to impede or completely block these
reactions, they may be able to slow or even stop the most
destructive activities of cancer cells.

     "This study helps explain one of the most common biochemical
characteristics of many cancer cells, namely, that they consume
unusually large quantities of a sugar known as glucose," says
Peter Pedersen, a Hopkins professor of biological chemistry and
co-author of a paper in the Journal of Biological Chemistry.
"This is particularly true of highly malignant cancer cells that
do the most harm to healthy tissues. In some cases, you can
almost predict how long a patient will live by looking at how
rapidly the patient's cancer cells consume glucose."

     Pedersen and his team have been exploring the link between
cancer cells' high glucose use and a protein known as hexokinase. 
Many cancer cells prefer to use a specific form of hexokinase to
begin breaking glucose down into energy and building materials, a
process known as glycolysis.

     This form, called tumor hexokinase type II, is overproduced
in many malignant cells but only found in low concentrations in
normal cells, says Pedersen.  His research team recently isolated
and worked out the DNA of a key portion of the hexokinase gene
responsible for this overproduction, an area known as the gene's
regulatory region.

     "If researchers can develop ways to suppress this region's
activity or knock it out completely, we may be able to slow the
growth of cancer cells by preventing them from getting energy
through glycolysis," he says.

     Scientists also could attempt to block factors that activate
the regulatory region of the gene. Knowing the region's sequence
will help scientists determine what chemicals or proteins this
area interacts with, and which of these factors activate it.  

     "If we disabled glycolysis and the cell then tried to turn
to its only other energy-producer, the mitochondria, that could
be a problem," Pedersen says. "But if we could knock out both of
those energy-producing processes, that would be a real killer. 
There's no way a cancer cell could survive that."

     Turning to the mitochondria may also be difficult for cancer
cells, because cancer cells are frequently located in low-oxygen
environments, and the mitochondria need oxygen to produce energy.

     Pedersen's team plans to investigate a possible link between
the regulatory region and an important tumor suppressor gene
known as the p53 gene. Some cancers are believed to begin when
cells with damaged DNA reproduce; p53 stops this reproduction,
helps direct repair of the DNA and directs a cell to kill itself
when the damage cannot be fixed.   

     "This link makes a lot of sense. If p53 becomes mutated or
turned off, and a cell becomes cancerous, then one of the first
steps the cell needs to take is to turn up hexokinase production,
so it can immediately start securing all the building blocks and
energy it needs to expand," Pedersen says.

     The team is also planning to investigate a possible link
between the tumor type II hexokinase gene and oncogenes, genes
that transform normal cells into cancerous cells.

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