Researchers led by an Indian American have found that an overexpressed protein protects human pancreatic cancer cells from being forced to devour themselves, removing one of the body’s natural defences against out-of-control cell growth.
The findings of scholars at the University of Texas’ M D Anderson Cancer Centre have been reported in the March issue of Molecular Cancer Research.
The protein tissue transglutaminase, known by the abbreviation TG2, previously has been found by researchers at the Centre and elsewhere to be overexpressed in a variety of drug-resistant cancer cells and in cancer that has spread from its original organ (metastasized), it said in a release.
“In general, you rarely see overexpression of TG2 in a normal cell,” says Kapil Mehta, professor in the M D Anderson Department of Experimental Therapeutics, who began 10 years ago studying TG2 as an inflammatory protein.
Mehta and colleagues in the past year have connected TG2 overexpress ion to drug-resistant and metastatic breast cancer, pancreatic cancer and melanoma.Mehta was educated in India at Punjab University and the Postgraduate Institute of Medical Education and Research, both in Chandigarh and also trained at the Indian Council of Medical Research in New Delhi and the CIBA-GEIGY Research Center in Bombay. He has been at Anderson Centre since 1985.
Expression of TG2 is tightly regulated in a healthy cell and is temporarily increased in response to certain hormones or stress factors, Mehta says. “However, constitutive expression of this protein in a cancer cell helps confer protection from stress-induced cell death.”
The mechanisms by which TG2 might promote drug-resistance and metastasis have remained elusive, the researchers note.The M D Anderson team shows in laboratory experiments that inhibiting the protein in pancreatic cancer cells leads to a form of programmed cell suicide called autophagy, or self-digestion.
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 tiny molecule known as small interfering RNA tailored to shut down expression of the protein.
In both cases, the result was a drastic reduction of TG2 expression (up to 94 %) and telltale signs of autophagy in the cancer cells, which became riddled with cavities called vacuoles.
“When autophagy occurs, a double membrane forms around a cell organ, or organelle. This autophagosome then merges with a digestive organelle called a lysosome and everything inside is consumed, leaving the vacuole and a residue of digested material. If enough of this happens, the cell dies” the Center says in the release.
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.