Apoptosis

Apoptosis is a tightly regulated form of cell death, also called the programmed cell death. Morphologically, it is characterized by chromatin condensation and cell shrinkage in the early stage. Then the nucleus and cytoplasm fragment, forming membrane-bound apoptotic bodies which can be engulfed by phagocytes. In contrast, cells undergo another form of cell death, necrosis, swell and rupture. The released intracellular contents can damage surrounding cells and often cause inflammation.

Apoptosis is an important process during normal development. It is also involved in aging and various diseases such as cancer, AIDS, Alzheimer's disease and Parkinson's disease.

The Mechanism

Figure 6-G-1. Comparison between active and inactive forms of caspases. Newly produced caspases are inactive. Specifically cleaved caspases will dimerize and become active.

During apoptosis, the cell is killed by a class of proteases called caspases. More than 10 caspases (web link) have been identified. Some of them (e.g., caspase 8 and 10) are involved in the initiation of apoptosis, others (caspase 3, 6, and 7) execute the death order by destroying essential proteins in the cell. The apoptotic process can be summarized as follows:

Activation of initiating caspases by specific signals (Figure 6-G-2).
Activation of executing caspases by the initiating caspases which can cleave inactive caspases at specific sites.
Degradation of essential cellular proteins by the executing caspases with their protease activity.

Figure 6-G-2. Coupling of caspase 8 or 10 to death receptors.

Death receptors: Fas/CD95, DR4/DR5, DR3, and TNFR (Tumor Necrosis Factor Receptor).
Adaptors: FADD (Fas-associated death domain protein) and TRADD (TNFR-associated death domain protein).
Activation: Binding of death ligands (FasL/CD95L, TRAIL/APO-2L, APO-3L and TNF) induces trimerization of their receptors, which then recruit adaptors and activate caspases.
Note: TRADD is involved only in the coupling between caspases and DR3 or TNFR. This adaptor can also recruit other proteins (web link) to inhibit apoptosis through the NF-kB pathway.

As shown in the above figure, a variety of death ligands (FasL/CD95L, TRAIL, APO-3L and TNF) can induce apoptosis. It is natural to see if they can kill cancer cells without affecting normal cells. TNF was first investigated in the 1980s for cancer therapy, but with disappointing results. Then CD95L (FasL) was tested in the 1990s. The results were still not satisfactory. Recently, TRAIL has been demonstrated to be highly selective for transformed cells, with minimal effects on normal cells. It could be an effective drug for both cancer and AIDS.

Review Articles:

Survivin, a cancer target with an emerging role in normal adult tissues - Mol Cancer Ther. 2006.

Targeted therapy by disabling crossroad signaling networks: the survivin paradigm - Mol Cancer Ther. 2006.

Necrotic death as a cell fate - Genes and Development, 2006.

Cell Death Independent of Caspases: A Review - Clin. Cancer Research, 2005.

Necrotic death as a cell fate - Genes and Development, 2005.

Pharmacological manipulation of cell death (Series, 10 articles) - J. Clin. Invest., 2005.

The Mitochondrial Death Pathway and Cardiac Myocyte Apoptosis - Circulation Research, 2004.

Inhibitor of Apoptosis Proteins: Translating Basic Knowledge into Clinical Practice - Cancer Research, 2004.

Caspase activation, inhibition, and reactivation: A mechanistic view - Protein Science, 2004.

Ways of dying: multiple pathways to apoptosis - Genes and Development, 2003.

Caspases signal not only apoptosis but also antigen-induced activation in cells of the immune system - Genes and Development, 2003.