HEALTHY CELLS VS. CANCER CELLS
In a normal, healthy cell the protein BCL2, located on the outer membranes of mitochondria, protects the cells from death by inhibiting apoptosis. As part of the stress response, the cytosolic protein BAX moves to the mitochondria and inhibits BCL2. Recall that BAX, PUMA and NOXA are genes switched on by p53 as part of the DNA damage response. This interaction between BAX and BCL2 has the effect of making the mitochondrial membrane permeable and releasing cytochrome c. Once released cytochrome c associates with APAF1 (apoptotic protease activating factor 1) to form the ‘apoptosome’, a multi-protein complex that activates a caspase cascade from caspase 9 to the major ‘executioner caspases’, caspase 3 and caspase 7. is that caspase-activated DNase (CAD) is released to digest nuclear DNA. Cancer cells typically have an elevated internal pH (~7.5) with respect to normal cells (~7.2) and, as cytochrome c-mediated caspase activity declines with increasing pH, this has the effect of conferring a degree of resistance to apoptosis. The fragments of DNA generated by caspase action can be separated on a gel as a ‘ladder’ – the characteristic signature of apoptosis.
The extrinsic pathway is essentially the response system to an extracellular suicide note. It is activated by death ligands binding to their receptors that are members of the tumour necrosis factor receptor (TNFR) superfamily. Following receptor activation, protein complexes form that lead to the activation of caspases 8 and 10 and the eventual phagocytosis of the cell.
The two pathways can cross-react through the action of caspase 8 on BID so that it can then bind to BCL2, inhibiting the anti-apoptotic action of BCL2. A family of inhibitor of apoptosis proteins (IAPs) bind to caspase 3 to prevent its activation – the most notable being survivin (encoded by BIRC5), which is commonly expressed in tumours and associated with resistance to chemotherapeutic drugs. Other proteins released from damaged mitochondria counteract IAPs (e.g. DIABLO), so that the overall apoptotic response reflects the balance between multiple factors that act in the two pathways.
It seems probable that self-destruction by apoptosis is the default option in multicellular animals and that the apoptotic pathways are normally repressed by survival signals, for example, from hormones and nutrients that sustain the expression of anti-apoptotic factors.
Apoptosis is one way in which cells can respond to stress, in particular, the stress of damaged DNA. Another type of stress response is a kind of cellular re-cycling referred to as autophagy, activated particularly as a response to nutrient deficiency. Enzymes break down organelles, including mitochondria, and use their constituent molecules in a re-cycling that, in effect, directs available energy into essential cellular processes. Autophagy probably occurs in every cell and is responsible for the degradation of most of the cell mass, but it may also permit cells to survive conditions in which they would otherwise perish. Tumour cells can use autophagy to ameliorate the effects of hypoxia (inadequate oxygen diffusion to the cell) and metabolic perturbation and they can also increase autophagic activity as a way of promoting resistance to anti-cancer agents.