Role of Dietary Antioxidants in p53-Mediated Cancer Chemoprevention and Tumor Suppression

Figure 1

A schematic of the p53-mediated apoptotic pathways in a mammalian cell. The apoptotic pathways involve intrinsic and extrinsic pathways. p53 activates the extrinsic pathway through the induction of the tumor necrosis factor receptor (TNF-R) superfamily that contains apoptotic death domains such as Fas, DR5, and PERP. Overexpression of p53 enhances levels of Fas at the cell surface by promoting the trafficking of the Fas receptor from the Golgi. Fas is activated by its ligand FasL, and DR5 is initiated by the ligand TRAIL. TNF-R is induced by p53 in response to DNA damage, which also promotes cell death through the caspase-9-mediated intrinsic pathway. The intrinsic pathway is dominated by the Bcl-2 family, including Noxa, Puma, and Bax. Bax is activated by BID to increase the mitochondrial outer membrane permeability, allowing efflux of cytochrome c to cytosol. BID is activated by cellular ROS and also cleaved by caspase-8. BID is a crossregulator between the extrinsic and intrinsic pathways. The released cytochrome c and Apaf-1 form a complex with pro-caspase-9 named apoptosome in which caspase-9 is activated. Caspase-8 is activated by death domains of the extrinsic pathway and cleaves proenzyme to form caspase-3, caspase-6, and caspase-7, which affect cell viability and overall apoptosis induced by p53. Abbreviations: Apaf-1: apoptotic protease-activating factor 1; Bax: Bcl-2-associated X protein; Bcl-2: B-cell lymphoma 2; BID: BH3 domain-only death agonist protein; DR5: death receptor 5; Fas: Fas cell surface death receptor; FasL: Fas ligand; Noxa: damage protein, a proapoptotic BH3-containing protein; p53: tumor suppressor; PERP: p53 apoptosis effector related to PMP22; Puma: p53 upregulated modulator of apoptosis; TNF-R: tumor necrosis factor receptor; TRAIL: tumor necrosis factor-related apoptosis-inducing ligand.