Major pathways of apoptosis. An extrinsic pathway of apoptosis (left) involves the stimulation through binding of death receptor (e.g., FasR and TNFR) to their respective ligands (e.g., FasL and TNF-α), recruiting adaptive proteins such as Fas-associated death-domain (FADD) and pro-caspase-8 (pro-C8), forming death-inducing signaling complex (DISC) and relaying signals to activation of effector caspases such as caspase-3 (C3), C6, and C7. In addition, Bid is also activated, which transduces these death signals to the intrinsic pathway. On the other hand, an intrinsic pathway of apoptosis is induced in response to cellular stresses such as DNA damage and ROS that increase the expression of proapoptotic Bcl-2 family proteins (e.g., Bid, Bad, and Bax), while repressing antiapoptotic Bcl-2 family proteins (e.g., Bcl-2, Bcl-xL, and Mcl-1), leading to an alteration in mitochondrial membrane potential and the release of cytochrome C (Cyto C). Proteins such as Apaf-1 and caspase-9 (C9) are activated, resulting in the formation of an apoptosome, which then stimulate the activation of effector caspases. NF-κB and JNK/ASK-1 also play a role in apoptotic signaling through the regulation of antiapoptotic molecules such as FLIP and Bcl-2.