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Blocking molecule benefits liver

Research finds slowed growth of tumors, less diabetes, obesity in mice

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A molecule normally involved in saving cells surprisingly helps chronic inflammation in the liver that can lead to tumors there, researchers at Georgia Health Sciences University reported Tuesday.

Blocking that molecule in mice not only impaired the tumor's progress but prevented the mice from developing diabetes and obesity even when fed a high-fat diet.

In a study published in Cell Metabolism , the researchers looked at a key molecule called heat shock transcription factor-1 that normally is involved in activating heat shock proteins that help cells survive environmental stress. But chronic inflammation leads to pre-malignant cells and what is often called metabolic syndrome: fatty liver disease, insulin resistance and obesity, conditions that favor the development of cancer.

"If you can change the metabolism of the body, and in particular of the liver to prevent fat accumulation in the liver, to increase the insulin sensitivity or to prevent insulin resistance, to improve the glucose metabolism, you can, in principle, interfere with process of (cancer development)," said Dr. Demetrius Moskophidis, a professor of biochemistry and molecular biology at Georgia Health Sciences University.

Mice bred to lack HSF-1 did not develop the fatty liver, had increased insulin sensitivity and did not gain much weight even when fed a high-fat diet.

Blocking the molecule had a surprising effect because "heat shock factor is supposed to protect the organism against environmental stress. And you would think if you remove it, it would be detrimental," said Dr. Nahid Mivechi, the director of the Center for Molecular Chaperone/Radiobiology and Cancer Virology at GHSU.

The absence of HSF-1 also activates an important energy-regulating molecule called AMP-activated protein kinase that also causes liver cells to produce less glucose and inhibits fat formation. The diabetes drug metformin also seems to activate that molecule.

Some drugs that inhibit the HSF-1 molecule already are being tested, but others need to be developed, Mivechi said.

In the brain, the molecule appears to help battle neurodegenerative diseases, so some companies are researching drugs to boost its action in the brain, she said.

"They are looking for activators of HSF-1 because that is good for neurodegenerative diseases and also inhibitors of HSF-1 for cancer, for chemotherapy," Mivechi said.

The trick would be to use either drug only temporarily, she said.

Because it is a key molecule called a molecular chaperone that helps alter proteins, the key will be to block it selectively, Moskophidis said.

"The big challenge for us as scientists is how we can modify this molecular chaperone to affect particular pathways without involving (it) in the disease progression, without affecting other housekeeping functions of the molecule," he said.


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