Intestinal Cells Protected from Radiation by Manipulation of Molecule

The research may lead to new strategies for protecting normal tissues from radiation during cancer therapies.

Although radiation is one of the most effective treatments for cancer, damage to the cells that line the gastrointestinal tract is a key limiting factor for patients undergoing pelvic or abdominal radiotherapy. The specific processes that underlie radiation-induced gastrointestinal toxicity, known as gastrointestinal (GI) syndrome, are not well understood. Earlier research has suggested that damage to intestinal stem cells and/or injury to intestinal blood vessel cells, called endothelial cells, are involved in the pathogenesis of GI syndrome.

The group of researchers, led by Drs. Jian Yu and Lin Zhang from the University of Pittsburgh Cancer Institute and School of Medicine (Philadelphia, PA, USA), found that the protein p53-upregulated modulator of apoptosis (PUMA) plays a major role in the radiation-induced damage of intestinal cells. PUMA is an established mechanism in the apoptosis pathway, a process by which cells undergo a type of programmed self-destruction.

Dr. Yu and colleagues, who published their findings in the June 2008 issue of the journal Cell Stem Cell, discovered that mice with a deficiency of PUMA exhibited impaired apoptosis in intestinal stem and progenitor cells, and enhanced intestinal regeneration following injury. The mutant mice therefore retained better intestinal integrity and survived longer following lethal doses of radiation. Although endothelial cells displayed a rapid induction of PUMA upon exposure to radiation, deletion of the protein did not change apoptosis in these specific cells.

These findings provide a mechanistic explanation of intestinal radiosensitivity and suggest that apoptosis of epithelial cells, and not endothelial cells, is the primary event that underlies the rapid onset of GI syndrome. "We were really excited to learn that deficiency in a single gene significantly protects against GI syndrome,” explained Dr. Yu. "Selectively curbing radiosensitivity in the normal tissues transiently by PUMA inhibitors might be particularly beneficial in cancer therapy.”


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