Protein Stops Suicide of Pancreatic Cancer Cells
CancerWise - June 2007
In laboratory tests, researchers have found that an excess amount of the protein TG2 prevents pancreatic cancer cells from devouring themselves, allowing the out-of-control cell growth that causes cancer.
Significance of results
“These results are from cell studies, not mouse studies or human clinical trials, but they are encouraging,” says study co-chair Gabriel Lopez-Berestein, M.D., a professor in M. D. Anderson’s Department of Experimental Therapeutics.
“Targeting TG2, or its activating protein PKC, or both, presents a novel and potentially effective approach to treating patients with pancreatic cancer,” he says of the findings published in the March issue of the journal Molecular Cancer Research.
Researchers at M. D. Anderson previously have connected overproduction of transglutaminase, a protein tissue known by the abbreviation TG2, to a variety of drug-resistant cancer cells and in cancer that has metastasized (spread from its original organ).
“In general, you rarely see overproduction of TG2 in a normal cell,” says Kapil Mehta, Ph.D., a professor in M. D. Anderson’s Department of Experimental Therapeutics who began studying TG2 as an inflammatory protein 10 years ago.
Production of TG2 is tightly regulated in healthy cells and is increased temporarily in response to certain hormones or stress factors.
“However, unregulated overproduction of this protein in a cancer cell helps confer protection from stress-induced cell death,” Mehta says.
To show TG2’s effect on pancreatic cancer cells, researchers inhibited its production.
Researchers did either of the following:
- Blocked another protein known to activate TG2
- Targeted TG2 with siRNA, a molecure that stops TG2 production
Both research methods caused:
- Up to 94% reduction of TG2 production
- Autophagy (self-digestion) of pancreatic cancer cells
If sufficient autophagy takes place, the cell dies.
The TG2 autophagy pathway is separate from a form of programmed cell death called apoptosis.
Apoptosis – Cells die because of damage to the nucleus and DNA, while other organelles (cell organs) are preserved.
Autophagy – Other organelles are degraded, while the nucleus is spared.
Mehta’s team also found that too high a level of TG2 activates a protein called nuclear factor-kB, which is known to play a role in regulating cell growth, metastasis and apoptosis. This could make TG2 an attractive target for other forms of cancer as well.
The mechanisms by which TG2 might promote drug-resistance and metastasis are unknown, the researchers note.
Researchers are studying TG2 as a pharmaceutical target and are now in the early stages of a mouse study that continues the research, Mehta says.
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