1,25-Dihydroxy vitamin D prevents tumorigenesis by inhibiting oxidative stress and inducing tumor cellular senescence in mice

Abstract

Human epidemiological studies suggest that 1,25(OH)₂D₃ deficiency might increase cancer incidence, but no spontaneous tumors have been reported in mice lacking 1,25(OH)₂D₃ or deficient in its receptor. In this study, we detected, for the first time, diverse types of spontaneous tumors in l,25(OH)₂D₃ deficient mice more than 1-year of age. This was associated with increased oxidative stress, cellular senescence and senescence-associated secretory phenotype molecules, such as hepatocyte growth factor, mediated via its receptor c-Met. Furthermore, 1,25(OH)₂D₃ prevented spontaneous tumor development. We also demonstrated that l,25(OH)₂D₃ deficiency accelerates allograft tumor initiation and growth by increasing oxidative stress and DNA damage, activating oncogenes, inactivating tumor suppressor genes, stimulating malignant cell proliferation and inhibiting their senescence; in contrast, supplementation with exogenous l,25(OH)₂D₃ or antioxidant, or knock-down of the Bmi1 or c-Met oncogene, largely rescued the phenotypes of allograft tumors. Results from this study suggest that 1,25(OH)₂D₃ deficiency enhances tumorigenesis by increasing malignant cell oxidative stress and DNA damage, stimulating microenvironmental cell senescence and a senescence-associated secretory phenotype, and activating oncogenes and inactivating tumor suppressor genes, thus increasing malignant cell proliferation. This study provides direct evidence supporting the role of vitamin D deficiency in increasing cancer incidence. Conversely, 1,25(OH)₂D₃ prevented spontaneous tumor development, suggesting that this inhibitory effect prevents the initiation and progression of tumorigenesis, thus provides a mechanistic basis for 1,25(OH)₂D₃ to prevent tumorigenesis in an aging organism. This article is protected by copyright. All rights reserved.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2BtVeFt