Before delving into modes of resistance to apoptosis, a brief review of the intrinsic pathway is in order. Activation of this pathway leads to permeabilization of the mitochondrial outer membrane and release of molecules, such as cytochrome c, that initiate apoptosis. The integrity of the mitochondrial outer membrane is determined by a delicate balancing act between pro-apoptotic and anti-apoptotic members of the BCL2 protein family. The pro-apoptotic proteins BAX and BAK are required for apoptosis and directly promote mitochondrial permeabilization. Their action is inhibited by the anti-apoptotic members of this family, which are exemplified by BCL2, BCL-XL, and MCL1. A third set of proteins, the so-called “BH3-only proteins,” which include BAD, BID, and PUMA, shift the balance between the pro-apoptotic and anti-apoptotic family members by neutralizing the actions of anti-apoptotic proteins like BCL2 and BCL-XL, thereby promoting apoptosis. When the sum total of all the BH3-only proteins “overwhelms” the protective BCL2/BCL-XL factors, BAX and BAK are activated and form pores in the mitochondrial membrane. These allow mitochondrial cytochrome c to
Deficiency of ROS growth factors Radiation and survival Chemicals signals
Fig. 6.25 Intrinsic pathway of apoptosis and major mechanisms used by tumor cells to evade cell death. (1) Loss of p53, either through mutation or through antagonism by MDM2. (2) Reduced egress of cytochrome c from mitochondria as a result of upregulation of anti-apoptotic factors such as BCL2, BCL-XL, and MCL-1. IAP, Inhibitor of apoptosis.
leak out into the cytosol, where it binds to APAF-1 and activates caspase-9, which in turn cleaves and activates executioner caspases such as caspase-3. Another group of factors that function as negative regulators of the intrinsic pathway is known as inhibitor of apoptosis proteins (IAPs), which bind caspase-9 and prevent apoptosis.
Within this framework, it is possible to illustrate the major mechanisms by which apoptosis is evaded by cancer cells (
Figure 6.25 ). These mainly involve loss of p53, the key component of early steps in the intrinsic pathway, and increased expression of anti-apoptotic members of the BCL2 family.
Loss of TP53 function. As already discussed, TP53 is commonly mutated in cancers at diagnosis, and the frequency of TP53 mutations is even higher in tumors that relapse after therapy. In addition to mutation of TP53, other lesions in cancers impair p53 function indirectly, most notably amplification of MDM2, which encodes an inhibitor of p53. Loss of p53 function prevents the upregulation of PUMA, a pro-apoptotic BH3-only member of the BCL2 family that is a direct target of p53. As a result, cells survive levels of DNA damage and cell stress that otherwise would result in their death.