Unmasking the interplay between mTOR and Nox4: novel insights into the mechanism connecting diabetes and cancer
Loading...
Files
Date
Journal Title
Journal ISSN
Volume Title
Publisher
John Wiley and Sons Inc
Abstract
Cancer was recently annexed to diabetic complications. Furthermore, recent studies suggest that cancer can increase the risk of diabetes. Consequently, diabetes and cancer share many risk factors, but the cellular and molecular pathways correlating diabetes and colon and rectal cancer (CRC) remain far from understood. In this study, we assess the effect of hyperglycemia on cancer cell aggressiveness in human colon epithelial adenocarcinoma cells in vitro and in an experimental animal model of CRC. Our results show that Nox (NADPH oxidase enzyme) 4-induced reactive oxygen species (ROS) production is deregulated in both diabetes and CRC. This is paralleled by inactivation of the AMPK and activation of the mammalian target of rapamycin (mTOR) C1 signaling pathways, resulting in 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) accumulation, induction of DNA damage, and exacerbation of cancer cell aggressiveness, thus contributing to the genomic instability and predisposition to increased tumorigenesis in the diabetic milieu. Pharmacologic activation of AMPK, inhibition of mTORC1, or blockade of Nox4 reduce ROS production, restore the homeostatic signaling of 8-oxoguanine DNA glycosylase/8-oxodG, and lessen the progression of CRC malignancy in a diabetic milieu. Taken together, our results identify the AMPK/mTORC1/Nox4 signaling axis as a molecular switch correlating diabetes and CRC. Modulating this pathway may be a strategic target of therapeutic potential aimed at reversing or slowing the progression of CRC in patients with or without diabetes.—Mroueh, F. M., Noureldein, M., Zeidan, Y. H., Boutary, S., Irani, S. A. M., Eid, S., Haddad, M., Barakat, R., Harb, F., Costantine, J., Kanj, R., Sauleau, E.-A., Ouhtit, A., Azar, S. T., Eid, A. H., Eid, A. A. Unmasking the interplay between mTOR and Nox4: novel insights into the mechanism connecting diabetes and cancer. FASEB J. 33, 14051-14066 (2019). www.fasebj.org. © FASEB.
Description
Keywords
Colorectal cancer, Dna damage, Mtorc1, Nadph oxidases, Amp-activated protein kinases, Animals, Antibiotics, antineoplastic, Blood glucose, Caco-2 cells, Diabetes mellitus, experimental, Gene expression regulation, neoplastic, Ht29 cells, Humans, Hypoglycemic agents, Male, Metformin, Mice, Mice, inbred c57bl, Mice, transgenic, Nadph oxidase 4, Sirolimus, Tor serine-threonine kinases, Up-regulation, Antidiabetic agent, Antineoplastic antibiotic, Hydroxymethylglutaryl coenzyme a reductase kinase, Mtor protein, human, Mtor protein, mouse, Nox4 protein, human, Nox4 protein, mouse, Reduced nicotinamide adenine dinucleotide phosphate oxidase 4, Target of rapamycin kinase, Animal, C57bl mouse, Caco-2 cell line, Drug effect, Experimental diabetes mellitus, Gene expression regulation, Genetics, Glucose blood level, Ht-29 cell line, Human, Metabolism, Mouse, Transgenic mouse, Upregulation