Share

Apoptotic pathways

Apoptosis is triggered through 2 signaling pathways²:

Intrinsic pathway

Extrinsic pathway

Intrinsic pathway

As its name suggests, the intrinsic, or mitochondrial, pathway is initiated from within the cell (Figure 3.1).³

This pathway is often activated in response to signals resulting from DNA damage, loss of cell-survival factors, or other types of severe cell stress. Normally, pro-apoptotic proteins are released from the mitochondria to activate caspase proteases and trigger apoptosis.³

Enlarge this image

When these pro-apoptotic signals are not released, the cell cannot die.¹ The intrinsic pathway hinges on the balance of activity between pro- and anti-apoptotic signals of the Bcl-2 family.¹⁴ Preclinical studies indicate that members of the Bcl-2 family regulate the permeability of the mitochondrial membrane and determine whether a pro- or anti-apoptotic signal will be released inside the cell.¹⁵

Research implies that in this cascade, the anti-apoptotic proteins (eg, Bcl-X_L) antagonize Bax and Bak by binding to their BH3 domains. This antagonism is relieved by BH3-only, pro-apoptotic proteins (eg, BIM, BID, BAD, NOXA, PUMA), which alternately bind to anti-apoptotic proteins, like Bcl-X_L. In normal cells, cellular stress would result in an upregulation of these BH3-only proteins in order to initiate apoptosis via the intrinsic apoptotic pathway.³

Currently, the intrinsic pathway is more widely implicated as a blockade to tumorigenesis.²

Extrinsic pathway

The extrinsic pathway begins outside the cell through activation of pro-apoptotic receptors on the cell surface. These are activated by molecules known as pro-apoptotic ligands.¹²

Preclinical studies show that ligand binding causes receptors to cluster and ultimately form a death-inducing signaling complex (DISC).¹²

Upon DISC activation, the extrinsic pathway has been seen to adopt the same effector caspase machinery as the intrinsic pathway.¹²