Cancer research
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Obesity is a well-known risk factor for colorectal cancer but precisely how it influences risks of malignancy remains unclear. During colon cancer development in humans or animals, attenuation of the colonic cell surface receptor guanylyl cyclase C (GUCY2C) that occurs due to loss of its paracrine hormone ligand guanylin contributes universally to malignant progression. In this study, we explored a link between obesity and GUCY2C silencing in colorectal cancer. ⋯ Mechanistic investigations revealed that obesity reversibly silenced guanylin expression through calorie-dependent induction of endoplasmic reticulum stress and the unfolded protein response in intestinal epithelial cells. In transgenic mice, enforcing specific expression of guanylin in intestinal epithelial cells restored GUCY2C signaling, eliminating intestinal tumors associated with a high calorie diet. Our findings show how caloric suppression of the guanylin-GUCY2C signaling axis links obesity to negation of a universal tumor suppressor pathway in colorectal cancer, suggesting an opportunity to prevent colorectal cancer in obese patients through hormone replacement with the FDA-approved oral GUCY2C ligand linaclotide.
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Phosphatases are key regulators of cellular signaling and as such play an important role in nearly all cellular processes governing diseases, including cancer. However, due to their highly conserved structure and highly charged and reactive catalytic site, they have been regarded as "undruggable." Fortunately, during the recent Europhosphatase meeting (Turku, Finland), it became clear that phosphatases can no longer be ignored as potential targets in cancer therapy. As reactivation of tumor-suppressor phosphatases or direct inhibition of phosphatases acting as oncogenes is becoming available, this class of enzymes can now be considered as feasible drug targets. Cancer Res; 76(2); 193-6. ©2016 AACR.