Reactive Oxygen Species and Apoptosis

Abstract

There is increasing evidence for the involvement of reactive oxygen species (ROS) in the regulation of central biological functions. Interaction between certain ROS and the generation of highly reactive ROS at desired locations, as well as their modulation by antioxidants and a variety of enzymes, warrant a hitherto unexpected degree of efficiency and specificity. ROS are involved in triggering and mediating apoptosis under physiological and pathophysiological conditions. This paper summarizes the major interdependencies of ROS and their physiological sources, and critically reviews the data on the evidence for the role of ROS during induction and execution of apoptosis. The focus is on the action of Superoxide anions, hydrogen peroxide, hydroxyl radicals, hypochlorous acid, nitric oxide and peroxynitrite. Glutathione represents one of the key elements during the regulation of apoptosis. It balances against ROS created by multiple signaling pathways, enzymatic reactions or mitochondria, and it inhibits sphingomyelinase, the key enzyme for the generation of ceramide. This second messenger is intrinsically interwoven with the generation of ROS and with activation of execution-caspases. Mitochondria are both the target and the source of ROS during induction and execution of apoptosis. The control of the mitochondrial permeability transition pore is therefore of central importance for the regulation of apoptosis. Tumor necrosis factor induces apoptosis through a versatile use of ROS. Similarly, ROS are involved in Apo/Fas-triggered or p53-mediated apoptosis at several distinct and synergistically acting steps. Direct apoptosis induction by TGF-beta depends on the action of ROS. Intercellular and intracellular ROS signaling is the basis for intercellular induction of apoptosis, a recently discovered system for the control of oncogenesis. It is based on specific apoptosis induction in transformed cells by their nontransformed neighbors. Superoxide anions released from transformed cells are the key for specific apoptosis induction. During intercellular signaling, a myeloperoxidase-analogous enzyme converts hydrogen peroxide (generated through dismutation of superoxide anions) into hypochlorous acid. This compound reacts with Superoxide anions at the membrane of the transformed cells to form the ultimate apoptosis-inducing hydroxyl radical. The limited diffusion pathway of Superoxide anions and the extreme reactivity of hydroxyl radicals ensure that apoptosis induction is restricted to transformed cells. The same signaling principle seems to be used when nitric oxide, a long-ranging signal is converted to the reactive peroxynitrite by Superoxide anions. These data indicate that natural antitumor mechanisms utilize similar signaling principles for specific apoptosis induction in transformed cells.