Reactive oxygen species: The good, the bad, and the enigma

Abstract

Work carried out primarily in the laboratory of Fabrizio d’Adda di Fagagna unveils the mitogenic properties of Ras-induced reactive oxygen species (ROS) and their relationship with the DNA damage response. Combined data from studies of cultured cells, zebrafish models, and clinical material consistently support a role of the RAS-RAC1-NOX4 axis in ROS induction, hyperproliferation, and senescence.

NADPH Oxidase-1 Plays a Key Role in Keratinocyte Responses to UV Radiation and UVB-Induced Skin Carcinogenesis

“…Similarly, we have previously shown that NOX1 activation in xeroderma pigmentosum type C (XPC)-deficient cells triggers neoplastic transformation of keratinocytes and premature skin aging (Hosseini et al, 2015b;Rezvani et al, 2011aRezvani et al, , 2011b. Moreover, up-regulation of NOXs in several cancers (Liu-Smith et al, 2014;Roy et al, 2015), as well as the capability of NOXs to modulate the proliferative capacity and replicative senescence in various cells (Block and Gorin, 2012;Ogrunc, 2014), support this notion. In this study, we report that NOX1 is up-regulated after acute and chronic UVB irradiation and that inhibition of its activation modulates the DDR network.…”

“…DDR inactivation allows the oncogeneinduced senescence to be bypassed and thus induces the proliferation of oncogene-expressing cells and their transformation (Bartkova et al, 2006;Di Micco et al, 2006). In support of this notion, inhibition of NOX-induced ROS production was reported to be an effective strategy to reduce hyperproliferation and to prevent DDR activation and oncogene-induced senescence in oncogenic Ras-expressing cells (Kodama et al, 2013;Ogrunc, 2014). On the contrary, NOX1 overexpression was shown to enhance the tumorigenic conversion of NIH3T3 cells (Suh et al, 1999) and to increase neoplastic progression of immortalized human keratinocytes (Chamulitrat, 2010).…”

“…To explain this, it was recently shown that oncogene activation in normal cells leads to an initial transient hyperproliferative phase, which is followed by the permanent establishment of cellular senescence (Di Micco et al, 2006) through a ROS/DDR-dependent process. Indeed, it has been proposed that the increased ROS levels in cells expressing an oncogene act as mitogenic signaling molecules and stimulate cell proliferation (Irani et al, 1997;Ogrunc, 2014;Park et al, 2014). The promitotic effect of NOX-mediated ROS could be related to the transient inactivation of protein tyrosine phosphatase through the oxidation of redox-sensitive cysteine residues (Caputo et al, 2012;Sancho and Fabregat, 2010).…”

“…Because accumulating evidence suggests that NOX-derived ROS contribute to the DDR network (Block and Gorin, 2012;Ogrunc, 2014), we wondered what impact NOX could have in the repair of UVB-induced DNA damage and apoptosis.…”

mTOR-Mediated Antioxidant Activation in Solid Tumor Radioresistance

“…Approximately 90% of intracellular ROS are estimated to be produced during OXPHOS in mitochondria [57]. Proper ROS levels stimulate cell proliferation, mediate signal cascades, and initiate immune responses, but excessive ROS levels lead to cell death [58]. erefore, when ROS are induced, the cell activates antioxidant mechanisms for homeostasis [59].…”