Scientists are using mouse models to develop TG2 as a pharmaceutical target.

An overexpressed protein protects human pancreatic cancer cells from going through autophagy, or self-digestion, removing one of the body’s natural defenses against out-of-control cell growth, report researchers at The University of Texas M. D. Anderson Cancer Center.

Overexpression of the protein TG2 has previously been connected to drug-resistant and metastatic breast cancer, pancreatic cancer, and melanoma. It’s mechanism of action, however, has not been well understood. In a study published in the March issue of Molecular Cancer Research, the M. D. Anderson team shows that inhibiting the protein in pancreatic cancer cells leads to a autophagy.

TG2 was inhibited in two separate ways. First, the researchers blocked another protein known to activate TG2. Secondly, they also directly targeted TG2 with a siRNA.

In both cases, the result was a reduction of up to 94% of TG2 expression and signs of autophagy in the cancer cells.
Gabriel Lopez-Berestein, M.D., professor of experimental therapeutics and study co-author, notes that the research also shows that the self-consuming cell death prevented by TG2 is independent of a prominent molecular pathway also known to regulate autophagy called the mammalian target of rapamycin.

“Targeting TG2, or its activating protein PKC, or both, presents a novel and potentially effective approach to treating patients with pancreatic cancer,” Dr. Lopez-Berestein notes.

“We are developing TG2 as a pharmaceutical target and are now working with a mouse model to that end,” says Kapil Mehta, Ph.D., professor at the M. D. Anderson Department of Experimental Therapeutics. The scientists caution, however, that the research in the mouse model remains is still in the early stages.

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