ROS‐generating oxidases Nox1 and Nox4 contribute to oncogenic Ras‐induced premature senescence

Abstract

Activated oncogenes induce premature cellular senescence, a permanent state of proliferative arrest in primary rodent and human fibroblasts. Recent studies suggest that generation of reactive oxygen species (ROS) is involved in oncogenic Ras-induced premature senescence. However, the signaling mechanism controlling this oxidant-mediated irreversible growth arrest is not fully understood. Here, we show that through the Ras/MEK pathway, Ras oncogene upregulated the expression of superoxide-generating oxidases, Nox1 in rat REF52 cells and Nox4 in primary human lung TIG-3 cells, leading to an increase in intracellular level of ROS. Ablation of Nox1 and Nox4 by small interfering RNAs (siRNAs) blocked the RasV12 senescent phenotype including b-galactosidase activity, growth arrest and accumulation of tumor suppressors such as p53 and p16Ink4a . This suggests that Nox-generated ROS transduce senescence signals by activating the p53 and p16Ink4a pathway. Furthermore, Nox1 and Nox4 siRNAs inhibited both Ras-induced DNA damage response and p38MAPK activation, whereas overexpression of Nox1 and Nox4 alone was able to induce senescence. The involvement of Nox1 in Ras-induced senescence was also confirmed with embryonic fibroblasts derived from Nox1 knockout mice. Together, these findings suggest that Nox1-and Nox4-generated ROS play an important role in Ras-induced premature senescence, which may involve DNA damage response and p38MAPK signaling pathways.

Areca nut exposure increases secretion of tumor‐promoting cytokines in gingival fibroblasts that trigger DNA damage in oral keratinocytes

“…ROS generation is mediated through activation of NADPH oxidase 45. In our study, NOX4 expression increased in cytokine‐treated IHOK, whereas NOX1 expression was reduced.…”

Reactive Oxygen Species, Vascular Noxs, and Hypertension: Focus on Translational and Clinical Research

“…The pathological role of Nox4 is unclear, although it has been implicated in hypertension, atherosclerosis, and cardiovascular and renal complications of diabetes and in remodeling of pulmonary arteries in pulmonary hypertension (181,206). Nox4-derivd ROS has also been suggested in cellular senescence and aging (104) and in insulin-mediated differentiation of adipocytes (177). Recent studies demonstrated that Nox4 may actually have protective effects, possibly through Nox4-derived H 2 O 2 , which may act as a vasodilator in some vascular beds (164,238).…”

NADPH oxidase 4 is a critical mediator in Ataxia telangiectasia disease

“…Several findings make it a good candidate. First, NOX4 is constitutively expressed and active in a large range of cells (9); second, it is localized to the immediate environment surrounding the nucleus so that ROS generated there could be responsible for the increased levels of oxidative DNA damage found in A-T cells (11)(12)(13); third, NOX4 has been found to be involved in senescence, a major phenotype exhibited by primary A-T cells (12,20,21).…”