Unmasking the interplay between mTOR and Nox4: novel insights into the mechanism connecting diabetes and cancer

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-29-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.

MicroRNA‐100 Enhances Autophagy and Suppresses Migration and Invasion of Renal Cell Carcinoma Cells via Disruption of NOX4‐Dependent mTOR Pathway

“… 13 Additionally, NOX4‐induced reactive oxygen species production is paralleled by activation of the mammalian target of rapamycin (mTOR) pathway, thus exacerbating colorectal cancer malignancy in a diabetic milieu. 14 Accumulating evidence has demonstrated the vitality of the activated mTOR pathway on the progression of RCC. 15 Therefore, we hypothesized the potential of miR‐100 to downregulate NOX4 and consequently regulate the mTOR pathway, thereby participating in the progression of RCC.…”

Effect of roasted peanut allergen Ara h 3 protein on the sensitization of Caco‐2 cells

“…The relative expression of ZO-1, occludin, and JAM-1 genes changed after incubation with Ara h 3-roasted. 32 These results suggest that the decrease in TEER value is not caused by cell death, but by the change in tight junction protein expression. ZO-1 protein is an important junction between occludin and the cytoskeleton, 33 and its destruction by Ara h 3-roasted can promote morphological changes in Caco-2 cells.…”

Histone deacetylase 3 inhibition alleviates type 2 diabetes mellitus-induced endothelial dysfunction via Nrf2

“…The GKT137831′s formula is C 21 H 19 ClN 4 O 2 , a member of the pyrazolopyridine dione family, which is an effective dual Nox1/4 inhibitor with an IC 50 of 110/140 nM. It is worth pointing out that Nox4 was the predominant Nox isoform in endothelial cells, and its expression was 100fold higher than that of Nox1, Nox2, or Nox [24] and the GKT137831 was a widely used Nox4 inhibitor for animal administration [33,34] as there is no specific Nox4 pharmacological inhibitor until now.…”