Linactolide
In mice, investigators found a high caloric diet turned off expression of a key hormone in the intestine, which led to deactivation of a tumor suppressor pathway. Genetic replacement of that hormone turned the tumor suppressor back on and prevented cancer development – even when mice continued to eat excess calories.
These findings position the use of the pill linaclotide (Linzess), which is structurally related to the lost hormone, as a therapeutic approach to preventing colorectal cancer in obese patients. The FDA approved linaclotide in 2012 to treat IBS with constipation as well as chronic idiopathic constipation (chronic constipation from unknown causes). “Our study suggests that colorectal cancer can be prevented in obese individuals with use of hormone replacement therapy – much as other diseases associated with hormone deficiency, such as loss of insulin in diabetes, can be treated,” Dr. Waldman says.
GUCY2C is a guardian of homeostatic integrity. GUCY2C is a transmembrane receptor with high expression in intestinal epithelial cells. GUCY2C is activated by guanylin (yellow) and uroguanylin (blue), and the exogenous ligand, ST (red), a heat-stable enterotoxin produced by enterotoxigenic Escherichia coli.
The risk of developing colorectal cancer in obese persons is about 50% greater, compared to risk in lean people. Scientists had thought the issue was one based on the amount of fat tissue and the associated unknown metabolic processes – excess calories that fuel cell energy and growth – but that did not turn out to be the case here, Dr. Waldman says.
Dr. Waldman is already involved in a multisite clinical study testing dose and side effects of linaclotide use in healthy volunteers. Investigators from the National Cancer Institute, Mayo Clinic, and Fox Chase Cancer Center are participating.
They used genetically engineered mice on different diets to conduct their investigation.
RESULTS: Obesity (either from excess fat or carbohydrate consumption, or both) is associated with loss of the hormone guanylin, produced in the intestine’s epithelium. The hormone turns on its receptor, guanylyl cyclase C (GUCY2C), which regulates processes underlying regeneration of the intestinal epithelium. Deactivation of the guanylin gene is common in colorectal cancers in both humans and animals. In that regard, morbidly obese patients exhibit an 80% decrease in guanylin gene expression compared to lean people, he says.
The researchers found the guanylin hormone receptor acts as a growth-controlling tumor suppressor, and without the hormone, the receptor is silenced. “This happens extremely early in development of the cancer,” Dr. Waldman says. “When the receptor is silenced, the epithelium becomes dysfunctional, setting up the conditions for cancer development.”
They created mice that carried a transgene that won’t allow the guanylin gene to be shut off. “Even in the setting of excess calories, from any diet source, tumors don’t develop,” he says.
Obese mice, compared to lean mice, were much more likely to silence the hormone and its receptor.
“These findings suggest that a drug like linaclotide, which acts like guanylin, can activate GUCY2C tumor-suppressing receptors to prevent cancer in obese patients,” he says. The researchers also showed excess calorie consumption can be reversed via calorie restriction, even in obese mice. http://www.eurekalert.org/pub_releases/2016-01/tju-lbo011316.php
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