Similarly, the gene encoding the tumor suppressor protein p53 is mutated in about 50% of human cancers so that it no longer promotes apoptosis or cell-cycle arrest in response to DNA damage. The lack of p53 function therefore enables the cancer cells to survive and proliferate even when their DNA is damaged; in this way, the cells accumulate more mutations, some of which make the cancer more malignant (discussed in Chapter 20). As many anticancer drugs induce apoptosis (and cell-cycle arrest) by a p53-dependent mechanism (discussed in Chapters 17 and 20), the loss of p53 function also makes cancer cells less sensitive to these drugs.
If decreased apoptosis contributes to many cancers, then we might be able to treat those cancers with drugs that stimulate apoptosis. This line of thinking has recently led to the development of small chemicals that interfere with the function of anti-apoptotic Bcl2 family proteins such as Bcl2 and BclXL. These chemicals bind with high affinity to the hydrophobic groove on anti-apoptotic Bcl2 family proteins, blocking their function in essentially the same way that BH3-only proteins do (Figure 18–13). The intrinsic pathway of apoptosis is thereby stimulated, which in certain tumors increases the amount of cell death.
Most human cancers arise in epithelial tissues such as those in the lung, intestinal tract, breast, and prostate. Such cancer cells display many abnormalities in their behavior, including a decreased ability to adhere to the extracellular matrix and to one another at specialized cell–cell junctions. In the next chapter, we discuss the remarkable structures and functions of the extracellular matrix and cell junctions.
Animal cells can activate an intracellular death program and kill themselves in a controlled way when they are irreversibly damaged, no longer needed, or are a threat to the organism. In most cases, these deaths occur by apoptosis: the cells shrink, condense, and frequently fragment, and neighboring cells or macrophages rapidly phagocytose the cells or fragments before there is any leakage of cytoplasmic contents. Apoptosis is mediated by proteolytic enzymes called caspases, which cleave specific intracellular proteins to help kill the cell. Caspases are present in all nucleated animal cells as inactive precursors. Initiator caspases are activated when brought into proximity in activation complexes: once activated, they cleave and thereby activate downstream executioner caspases, which then cleave various target proteins in the cell, producing an amplifying, irreversible proteolytic cascade.
Cells use at least two distinct pathways to activate initiator caspases and trigger a caspase cascade leading to apoptosis: the extrinsic pathway is activated by extracellular ligands binding to cell-surface death receptors; the intrinsic pathway is activated by intracellular signals generated when cells are stressed. Each pathway uses its own initiator caspases, which are activated in distinct activation complexes: in the extrinsic pathway, the death receptors recruit caspase-8 via adaptor proteins to form the DISC; in the intrinsic pathway, cytochrome c released from the intermembrane space of mitochondria activates Apaf1, which assembles into an apoptosome and recruits and activates caspase-9.
Intracellular Bcl2 family proteins and IAP proteins tightly regulate the apoptotic program to ensure that cells kill themselves only when it benefits the animal. Both anti-apoptotic and pro-apoptotic Bcl2 family proteins regulate the intrinsic pathway by controlling the release of mitochondrial intermembrane proteins, while IAP proteins inhibit activated caspases and promote their degradation.