Apoptotic Pathway

Apoptosis occurs through two main signalling pathways, which are extrinsic and intrinsic apoptotic pathways. Many studies have been carried out to decipher the molecular pathways involved in the regulation of apoptosis in order to develop effective therapeutic approaches.

Intrinsic Apoptotic Pathway

There are many ways to induce apoptosis. Any stimuli that cause oxidative stress, mitochondrial disturbances and DNA damage may stimulate the intrinsic pathway. For example, cancer therapeutic agents, hypoxia, and ionizing irradiation can trigger intrinsic pathway of apoptosis. When the mitochondrion is damaged, the outer membrane will become permeable and facilitates cytochrome c release into cytoplasm. Then, the cytochrome c will bind to the caspase adaptor, Apaf-1 (apoptotic protease-activating factor-1), to form the apoptosome complex and consequently triggering the apoptotic cascade by activating procaspase 9. The newly activated caspase 9 activates many downstream effector caspases like caspase 3, caspase 6 and caspase 7, leading to DNA fragmentation and cell death. Therefore, caspases play essential role in intrinsic apoptotic pathway.

Another mechanism of inducing apoptosis is to alter its threshold by modulating pro-apoptotic and anti-apoptotic members of Bcl-2 family. The Bcl-2 family is another group of key players in intrinsic apoptotic pathway. The Bcl-2 family consists of more than 20 members of pro-apoptotic proteins and anti-apoptotic proteins. Members of the Bcl-2 family function as agonists or antagonists to each other as they can form homo- or heterodimers. Pro-apoptotic members of Bcl-2 family such as Bax, Bak, Bok, Bid and Bim can induce the release of cytochrome c from mitochondria. While anti-apoptotic members like Bcl-2, Bcl-XL and so on can bind to Apaf-1 to inactivate the intrinsic pathway. However, the pro-apoptotic members can dissociate the complex of anti-apoptotic members and Apaf-1 to allow the Apaf-1 to activate the caspase 9 and lead to subsequent apoptotic process. At the same time, Bax and Bak can promote apoptosis by triggering the release of Smac/DIABLO protein from mitochondria and subsequently inactivate the inhibitors of apoptosis proteins (IAP).

Extrinsic Apoptotic Pathway

On the other hand, the extrinsic apoptotic pathway is induced by ligand binding of death receptors. The major ligand-death receptor system include tumor necrosis factor (TNF) with tumor necrosis factor receptor 1 (TNFR1), Fas ligand with Fas, and TRAIL with TRAIL receptors. The binding of the receptors with the ligands will induce the receptor oligomerization and recruitment of death signal adaptor proteins. These formed a complex termed DISC (death-inducing signalling complex), which can bind to initiator caspases like caspase 8 and caspase 10. Consequently, the caspase cascade will be triggered to activate the caspase 3, caspase 7 and caspase 9, and leading to apoptotic events.

Relationship Between Intrinsic and Extrinsic Apoptotic Pathway

According to cancer research, there is extensive crosstalk that occurs between the intrinsic and extrinsic apoptotic pathways. The activation of caspase cascade is the crucial component in the death process in either pathway. The pro-apoptotic and anti-apoptotic proteins can work together to maintain a dynamic balance between the survival and death of the cell.

In conclusion, it can be useful in cancer therapy if there are some efforts that can repress the anti-apoptotic proteins or boost up the pro-apoptotic members (Liang et. al., 2009). Triggering an effective apoptotic pathway on cancer cells is the most effective way to eliminate the cancer cells naturally.