Microbiology professor Steven
Blanke (center), graduate student Prashant Jain (left) and
postdoctoral researcher Tamilselvam Batcha found that a factor
produced by the bacterium H. pylori directly activates an
enzyme in...
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CHAMPAIGN, lll. — Researchers report that Helicobacter
pylori, the only bacterium known to survive in the harsh
environment of the human stomach, directly activates an enzyme in
host cells that has been associated with several types of cancer,
including gastric cancer.
Chronic infection with H. pylori is a well-documented
risk factor for several forms of gastric cancer, but researchers
have not yet determined the mechanisms by which specific bacterial
factors contribute to cancer development. Nearly one-half of the
world's population is infected with H. pylori, and gastric
cancer is one of the leading causes of cancer-related death.
The new study, in Proceedings of the National Academy of
Sciences, is the first to show that a factor produced by the
bacterium directly activates poly(ADP-ribose) polymerase-1
(PARP-1), an enzyme found primarily in the nucleus of animal cells.
PARP-1 is a regulator of the host's inflammatory response and host
cell death, both of which are hallmarks of H. pylori
infection.
PARP-1 is best known as a normal part of the cellular machinery
that repairs damaged DNA. But in certain types of cancer this
enzyme actually enhances tumor survival and undermines
chemotherapies designed to damage DNA in cancer cells. A recent
human clinical trial found that drugs that inhibited PARP-1 reduced
tumor growth in breast-cancer patients with mutations in certain
DNA-repair (BRCA-1 and BRCA-2) genes. BRCA-1 mutations also are
associated with an increased risk of stomach cancer.
The new study tackled the most urgent health problem associated
with H. pylori infection, said Steven Blanke, a University
of Illinois professor in the department of microbiology and
Institute for Genomic Biology and principal investigator on the
study.
"What is it about sustained infection with H. pylori that
leads in some cases to the development of stomach cancer?" he
said.
Like other disease-causing bacteria, H. pylori have
evolved to evade the body's defenses and even modify host proteins
to help the bacteria survive.
Blanke and his graduate student Carlos Nossa previously had
demonstrated that a protein factor released by H. pylori
modifies an unidentified host protein in a manner consistent with
an enzymatic reaction known as ADP-ribosylation. Other bacterial
toxins, including cholera toxin and diphtheria toxin
"ADP-ribosylate" host proteins in ways that enhance the survival or
transmission of the bacteria that produce them.
"We were very excited about this finding, which we published in
2006," Blanke said. "We thought we had discovered a new toxin."
ADP-ribosylation can be tracked by incorporating a radio-isotope
of phosphorous (32P) into a small molecule that is
required for the reaction. During ADP-ribosylation, H.
pylori transfers the 32P from the labeled molecule
to a host protein, thereby tagging it with a radioactive
fingerprint. Further analyses revealed that the radio-labeled host
protein was PARP-1.
At this point, the team believed that the bacterium was
ADP-ribosylating PARP-1. But when they genetically altered the
functional regions of PARP-1, they completely blocked the H.
pylori-dependent modification. Since PARP-1 also possesses
poly-ADP-ribosylation enzymatic activity, which is necessary for
its regulatory and DNA-repair function in cells, the team realized
that something in the H. pylori arsenal was directly
activating the PARP-1 enzymatic activity, rather than
ADP-ribosylating it as they first suspected.
Additional studies validated that H. pylori indeed
activates PARP-1 during infection of human gastric cells.
"These studies potentially provide a direct molecular link
between H. pylori infection and the activation of a factor
known to be involved in the survival of cancerous cells," Blanke
said. "Although PARP-1 can potentially be activated indirectly as a
host cell response to some infections, this is the first example of
a bacterium that can activate PARP-1 directly, perhaps in this case
as a mechanism for H. pylori to promote inflammation and/or
the death of host cells during long-term infection."
The researchers are working to identify the bacterial factor
that activates PARP-1, which would be a promising target for drugs
to treat or prevent the problems associated with long-term
infection with H. pylori, Blanke said.
SOURCE