Reactive oxygen species-dependent signaling regulates cancer

Abstract

Historically, it has been assumed that oxidative stress contributes to tumor initiation and progression solely by inducing genomic instability. Recent studies indicate that reactive oxygen species are upregulated in tumors and can lead to aberrant induction of signaling networks that cause tumorigenesis and metastasis. Here we review the role of redox-dependent signaling pathways and transcription factors that regulate tumorigenesis.

Fig. 1

ROS levels determine cellular outcomes. Induction of ROS at lower levels leads to activation of signaling pathways responsible for regulating cellular proliferation and growth. Conversely, high levels of ROS generation can lead to DNA damage, resulting in genomic instability

Fig. 2

ROS can activate pathways that regulate tumorigenesis. ROS generated from mitochondria or NADPH oxidases can activate PI3K or ERK MAPK signaling pathways and the transcription factors HIFs to regulate metabolism, angiogenesis, survival, cell growth, and proliferation

Fig. 3

ROS signaling in normal versus cancer cells. In normal cells, low levels of ROS can regulate controlled proliferation while high levels of ROS lead to cell death or senescence. Cancer cells with mutations in tumor suppressors can evade ROS induction of cell death or senescence. Thus, cancer cells exhibit high levels of ROS leading to uncontrolled cellular proliferation

Fig. 4

ROS can induce tumor metastasis. ROS generated from the mitochondria under hypoxic conditions can activate HIF-1α, which can lead to subsequent activation of the transcription factor, TWIST, resulting in EMT. Mitochondrial ROS during hypoxia can inhibit GSK3β, resulting in upregulation of SNAIL. ROS are also generated from an alternate spliced variant of Rac1β, which leads to activation of the transcription factor, SNAIL, resulting in EMT