R4.5c: Resisting Cell Death

Apoptosis may be achieved by the intrinsic or extrinsic pathways. An alternative pathway is when cytotoxic T-lymphocytes induce apoptosis with granzyme B.

Extrinsic Pathway

The extrinsic pathway requires expression of death receptors and a functioning death-inducing signalling complex. This activates caspase-8, which is then able to trigger the intrinsic pathway or directly activate caspase-3, the executioner caspase. Cancer cells typically reduce expression of the death receptors or overproduce proteins (FLIP) that bind to the internal death-inducing signalling complex.

Intrinsic Pathway

The intrinsic pathway relies on the interactions of the BCL2 family of apoptotic proteins. These include BAX and BAK, which promote apoptosis by increasing the permeability of the mitochondrial membrane. BCL2 and BCL-XL are anti-apoptotic proteins which oppose the action of BAX/BAK. Finally, a third set of BH3-only proteins regulate the balance between the pro- and anti-apoptotic proteins and may also respond to death stimuli.
Tumour cells overcome the intrinsic pathway reducing expression of the pro-apoptotic and BH3-only proteins, or by increasing the expression of BCL2 and the related anti-apoptotic proteins. The typical example is follicular lymphoma, where the BCL2 is translocated next to the promoter region for immunoglobulin. This leads to heightened expression of BCL2 and therefore increased lymphocyte survival.
TP53 is a vital gene in the activation of the intrinsic pathway through its interaction with BAX and BAK. Deactivations of TP53 hamper the cells ability to cause apoptosis through the intrinsic pathway.


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Bibliography
1. Hanahan, D., & Weinberg, R. A. (2000). The hallmarks of cancer. Cell, 100(1), 57–70.
2. Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of Cancer: The Next Generation. Cell, 144(5), 646–674. doi:10.1016/j.cell.2011.02.013