Apoptosis and cancer signaling pathway
Apoptosis, or programmed cell death, is a process that maintains tissue homeostasis by removing damaged or unwanted cells. In cancer, this process often fails, allowing abnormal and transformed cells to survive and multiply. Our pathway poster explores how apoptosis and cancer signalling pathways are regulated, offering insights into disease progression and treatment.
What is apoptosis (programmed cell death)?
Apoptosis is a tightly regulated process leading to orderly cell dismantling and removal. Unlike necrotic cell death, apoptosis is well-regulated and plays key roles in development, immune function, and tissue homeostasis. Normal cells undergo apoptosis in response to a variety of cell intrinsic and cell extrinsic stimuli, in order to maintain a balance between cell survival and death1.
Apoptotic cells show distinct features like DNA fragmentation, blebbing of the cell and plasma membranes, and formation of apoptotic bodies – cell fragments resulting from apoptotic cell death2. Specific cell surface markers, such as phosphatidylserine, distinguish apoptosis from other forms of cell death, such as necrosis. One key element of apoptosis is the removal of cells without causing tissue inflammation. Phagocytic and inflammatory cells clear apoptotic cells and apoptotic bodies efficiently without causing further damage to the tissue microenvironment.
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The role of the Bcl-2 family in apoptosis
The Bcl-2 family of proteins centrally regulates apoptosis via the intrinsic pathway. This family includes pro-apoptotic and anti-apoptotic members that control mitochondrial outer membrane integrity. Expression and activation of the different family members help to balance signals that regulate the induction of apoptosis. Cell intrinsic internal signals, like DNA damage or oxidative stress, activate the intrinsic pathway3.
Pro-apoptotic proteins such as BCL-2-associated X protein (Bax) and BH3-interacting-domain death agonist (Bid) promote mitochondrial membrane permeabilization, releasing cytochrome c and Apaf-1 into the cytoplasm, triggering the caspase cascade.
Caspases are a family of cysteine proteases that play critical roles in activating, tuning, and executing cellular apoptosis. In the intrinsic pathway, the first caspase to be activated is caspase-9, which undergoes self-cleavage and triggers a cascade involving active further effector caspases like caspase-3, executing apoptosis and leading to cell death. Anti-apoptotic proteins like Bcl-2 and Bcl-xL stabilize the mitochondrial membrane, counteracting apoptosis. Many cancers overexpress Bcl-2, helping tumor cells evade apoptosis4.
p53: the tumor suppressor gene and guardian of the genome
The p53 protein is a key tumor suppressor responding to cellular stress such as DNA damage. Activation of p53 induces the expression of genes associated with DNA repair and halts cell cycle progression to allow genetic damage to be repaired. Alternatively, p53 activation can trigger apoptosis if the damage is irreparable. By regulating the cell cycle and apoptosis, p53 prevents uncontrolled cell division5.
In cancer, p53 is the most frequently mutated or inactivated gene. By disabling this checkpoint, neoplastic cells are able to undergo controlled cell division, contributing to tumor development and cancer therapy resistance6.
Death receptor signaling
Apoptosis also involves death receptors on the cell surface, such as TNFR1 DR4, and DR5, members of the tumor necrosis factor (TNF) family. Ligands like TRAIL or TNFα activate these receptors, recruiting adaptor proteins like FADD and TRADD to form the death-inducing signaling complex (DISC). DISC activation triggers caspase-8 and initiation of the caspase cascade7.
The extrinsic pathway transduces external death signals to the apoptotic machinery, directly activating caspase-3 downstream or amplifying the mitochondrial apoptosis pathway to the same effect. In addition to perforin and granzyme-associated mechanisms, cytotoxic T cells induce apoptosis in target cells, such as virus-infected or tumor cells, via the extrinsic pathway. Enhancing the killing of transformed cells by cytotoxic T and NK cells is a key aim of tumor immunotherapy8.
Inhibitors of apoptosis proteins (IAPs)
IAPs prevent apoptosis by inhibiting caspases, blocking both intrinsic and extrinsic pathways. They contain Baculovirus IAP repeat (BIR) domains that suppress caspase 3, 7, and 9. Overexpression of IAPs is common in cancers, contributing to resistance against apoptosis-inducing treatments9.
Therapies targeting IAPs, like Smac mimetics, mimic mitochondrial proteins that neutralize IAPs, restoring caspase activation and apoptotic responses in cancer cells10.
NF-κB and apoptosis resistance
The NF-κB pathway regulates apoptosis and is known for roles in inflammation and immune system function. NF-κB promotes cell survival by inducing anti-apoptotic genes, including Bcl-2 and IAPs. Constitutive NF-κB activation in many cancers contributes to apoptosis resistance and tumor progression. Targeting NF-κB may sensitize cancer cells to apoptosis and enhance therapy effectiveness11.
Connecting the dots: apoptosis and cancer therapy
Cancer progression and tumor growth are maintained by the evasion of apoptosis by cancer cells. Signalling pathways regulating cell survival and migration influence cancer metastasis by allowing cancer cells to survive in microenvironments that would normally induce cell death. It is also known now that many tumours harbour areas of necrotic tissue, in part because of a failure of cancer cells to succumb to regulated apoptosis. These necrotic regions of tumours have many deleterious effects, including the induction of tumorigenesis and inflammation. Much cancer research focuses on how cancer cells evade apoptosis and promote tumor formation12.
Many cancer types, including breast, lung, prostate, and gastric cancer, have specific metabolic and signalling alterations that prevent cells from undergoing normal apoptosis. Many emerging therapies, including several in Phase II trials, target these tumour-specific alterations. Targeting the characterised defects in apoptosis that distinguish normal and cancer cells in different tumour types is crucial for targeted therapies with fewer side effects14,15. Inhibiting apoptosis can contribute to neurodegenerative diseases like Alzheimer's.
References
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3. Qian, S. et al. The role of BCL-2 family proteins in regulating apoptosis and cancer therapy. Front. Oncol. 12, 985363 (2022).
4. Wolf, P. et al. Pro-apoptotic complexes of BAX and BAK on the outer mitochondrial membrane. Biochim. Biophys. Acta Mol. Cell Res. 1869, 119317 (2022).
5. Williams, A. B. & Schumacher, B. p53 in the DNA-damage-repair process. Cold Spring Harb. Perspect. Med. 6, a026070 (2016).
6. Marei, H. E., Althani, A., Afifi, N. et al. p53 signaling in cancer progression and therapy. Cancer Cell Int. 21, 703 (2021).
7. Thorburn, A. Death receptor-induced cell killing. Cell. Signal. 16, 139–144 (2004).
8. Yanumula, A. & Cusick, J. K. Biochemistry, Extrinsic Pathway of Apoptosis. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan–. Available from: https://www.ncbi.nlm.nih.gov/books/NBK560811/
9. Nachmias, B. et al. The inhibitor of apoptosis protein family (IAPs): an emerging therapeutic target in cancer. Semin. Cancer Biol. 14, 231–243 (2004).
10. Sun, Q. et al. Smac modulates chemosensitivity in head and neck cancer cells through the mitochondrial apoptotic pathway. Clin. Cancer Res. 17, 2361–2372 (2011).
11. Guo, Q., Jin, Y., Chen, X. et al. NF-κB in biology and targeted therapy: new insights and translational implications. Signal Transduct. Target. Ther. 9, 53 (2024).
12. Plati, J. et al. Apoptotic cell signaling in cancer progression and therapy. Integr. Biol. 3, 279–296 (2011).
13. Carneiro, B. A. & El-Deiry, W. S. Targeting apoptosis in cancer therapy. Nat. Rev. Clin. Oncol. 17, 395–417 (2020).
14. You, M., Xie, Z., Zhang, N. et al. Signaling pathways in cancer metabolism: mechanisms and therapeutic targets. Signal Transduct. Target. Ther. 8, 196 (2023).
15. Mustafa, M. et al. Apoptosis: a comprehensive overview of signaling pathways, morphological changes, and physiological significance and therapeutic implications. Cells 13, 1838 (2024).