Intrinsic pathway
As its name suggests, the intrinsic pathway is initiated from within the cell (Figure 2.3). This is usually in response to cellular signals resulting from DNA damage, a defective cell cycle, detachment from the extracellular matrix, hypoxia, loss of cell survival factors, or other types of severe cell stress. This pathway involves release from the mitochondria of pro-apoptotic proteins that activate caspase enzymes, which ultimately trigger apoptosis.7-10
Figure 2.3. The intrinsic apoptosis pathway.Click here to view a PDF of this image.
Adapted from Ashkenazi 2002. Reproduced with permission from Nature Reviews Cancer.
The intrinsic apoptotic pathway hinges on the balance of activity between pro- and anti-apoptotic members of the BCL2 superfamily of proteins (Figures 2.4 and 2.5) which act to regulate the permeability of the mitochondrial membrane.11 The anti-apoptotic BCL2 proteins BCL2 and BCLXL act to prevent permeabilization of the mitochondrial outer membrane by inhibiting the action of the pro-apoptotic multi-domain BCL2 proteins BAX (a cytosolic protein) and BAK (found in the mitochondrial membrane).12 Overexpression of BCL2 and BCLXL is known to be associated with a number of human malignancies.7,13,14 Other pro-apoptotic BCL2 family members, including the BH3-only proteins PUMA and NOXA, act as cytosolic sensors of cell damage or stress.15
Figure 2.4. Pro- and anti-apoptotic members of the BCL2 superfamily of proteins.Click here to view a PDF of this image.
Adapted from Mayer and Oberbauer 2003. Reproduced with permission from News in Physiological Sciences.
Figure 2.5. The role of BCL2 proteins in cell survival and apoptosis.Click here to view a PDF of this image.
The intrinsic pathway begins with cell stress triggering the active transcriptional upregulation of specific members of the pro-apototic BCL2 protein family involved in the promotion of apoptosis, such as the BH3-only proteins PUMA and NOXA. These in turn activate the multi-domain proapoptotic proteins BAX or BAK which move to the mitochondrial membrane and disrupt the function of the anti-apoptotic BCL2 proteins thereby allowing permeabilization of the mitochondrial membrane.16 Cytochrome c and the pro-apoptotic protein SMAC/DIABLO are then able to leak from the intermembrane space of the mitochondria into the cytosol.16 This is why the intrinsic pathway is sometimes referred to as the mitochondrial pathway.
Cytochrome c binds the adaptor apoptotic protease activating factor-1 (APAF1), forming a large multi-protein structure known as the apoptosome. The apoptosome then recruits and activates caspase 9, which, in turn, activates the downstream effector caspases, including caspase 3, 6, and 7, leading to apoptosis.16
Under normal conditions, caspase activity is held in check by a protein family known as inhibitor of apoptosis proteins (IAPs), of which at least 10 have been identified, including XIAP, cIAP1, cIAP2, ILP2, MLIAP, SURVIVIN and BRUCE.4,5 IAPs are characterized by the presence of between 1 and 3 specific domains termed baculoviral repeats (BIRs) which are directly involved in their caspase-inhibitory activity. While not directly involved in apoptotic signaling per se, some of these proteins prevent cell death by suppressing endogenous initiator and effector caspase activity (Figure 2.6). As part of the intrinsic apoptosis pathway, the SMAC/DIABLO protein released from the mitochondria promotes apoptosis by directly interacting with IAPs and disrupting their ability to inactivate the caspase enzymes (Figure 2.6).16,17
Figure 2.6. Suppression of apoptosis by IAPs in the absence of pro-apoptotic signals.Click here to view a PDF of this image. Adapted from Ashkenazi 2002. Reproduced with permission from Nature Reviews Cancer.
Emerging evidence also suggests that IAPs may play a role in modulating cell division.18 The IAPs Survivin and c-IAP1 are overexpressed in several malignancies.18