ROS, stress-activated kinases and stress signaling in cancer

Abstract

Anticancer therapy is frequently efficient in early stages of the disease, whereas advanced tumors are usually resistant to the same treatments. The molecular basis for this change is not entirely understood. Many anticancer agents are DNA- or cytoskeleton-damaging drugs that show some specificity towards dividing cells. However, recent studies show that these agents also activate stress-signaling cascades that may play a role in eliciting the observed therapeutic effects. We discuss recent findings that suggest that induction of stress signaling in oncogenically transformed cells is integrated into apoptotic pathways. Reactive oxygen species (ROS) and stress-activated protein kinases (SAPKs), which are potentiated in recently transformed cells, emerge as key effectors of cell death. In advanced tumors, however, these agents are downregulated and, consequently, death signaling is suppressed. Such changes in ROS and SAPK activity levels during the course of tumor development may underlie the changes in responsiveness to anticancer therapy.

Fig. 1. Modulation of apoptosis sensitivity during oncogenesis. Most normal cells are relatively resistant to stress caused by DNA- or cytoskeleton-damaging agents. Following moderate levels of damage, these cells usually initiate cell-cycle arrest, which is succeeded by damage repair. During the process of oncogenic transformation, both proliferative and stress signals are enhanced, leading to sensitization to apoptotic stimuli. This is the basis for the selectivity of anticancer agents towards neoplastic cells. As tumor cells evolve, they undergo stress-driven selection, which finally endows them with anti-apoptotic armor. Thus, advanced tumor cells usually display a high degree of resistance to stress signals.

Fig. 2. A model that illustrates how the dysregulation of ROS and SAPKs in transformed cells may set the cellular response to anticancer agents. In non-neoplastic cells, ROS and SAPK activities are usually maintained at low levels (green). Following exposure to stress stimuli, ROS and SAPK activities are induced (red), leading to cell-cycle arrest, repair and survival. During oncogenic transformation, ROS and SAPK activities rise to levels that support cell growth (green). In these rapidly proliferating cells, exposure to stress results in an amplified stress response (further increase in ROS and SAPKs) that induces cell death (red). In advanced cancer (not shown), ROS/SAPK signaling is suppressed to confer protection from death signals (see text for details). Consequently, advanced tumor survival is maintained even when cells experience stress and damage.

Moran Benhar, Moran Benhar & Alexander Levitzki