Lecture 11 - Resisting Cell Death Immortality 2024

Introduction to Apoptosis and Cancer

Apoptosis, also known as programmed cell death, is a vital process that helps maintain cellular homeostasis by allowing organisms to eliminate damaged, unnecessary, or potentially harmful cells. This carefully regulated process plays a critical role in various biological processes, including development, immune response, and tissue homeostasis. In cancer, the balance between cell proliferation (growth) and apoptosis is disrupted, resulting in uncontrolled cellular growth and survival of cells that would normally undergo programmed cell death.

Oncogenes and Tumor Suppressor Genes

Oncogenes in Cancer

  • Function: Oncogenes are mutated forms of normal genes (proto-oncogenes) that promote cell proliferation and inhibit apoptosis.

  • Result: The activation of oncogenes, often through mutations, amplifications, or chromosomal translocations, leads to increased cell division, contributing to tumor growth and cancer progression.

Tumor Suppressor Genes in Cancer

  • Function: Tumor suppressor genes typically inhibit the cell cycle, promote apoptosis, and maintain genomic stability.

  • Result: Loss of function in these genes, such as p53 and Rb, leads to unregulated cell cycle progression and resistance to apoptosis, driving tumorigenesis.

Importance of Apoptosis

Apoptosis is essential in several biological functions:

  • Maintains tissue homeostasis: Controls the number of cells in tissues, ensuring optimal tissue structure and function.

  • Defends against infections: Eliminates virus-infected or malfunctioning cells, protecting the organism from disease.

  • Removes damaged cells: Crucial for preventing cancer progression by eliminating cells with DNA damage or other malignant traits.

  • Promotes normal development: Plays an essential role in embryogenesis and organogenesis, such as shaping limb and organ structures by removing excess cells.

Developmental Studies in Apoptosis

C. elegans Research

Research in the nematode C. elegans has been pivotal in understanding apoptosis. Scientists identified that out of 1090 cells generated during its development, 130 undergo apoptosis. These studies helped map the core apoptotic pathways through mutagenesis, leading to the identification of key genes involved in apoptosis, known as CED genes. For his contributions to this field, Robert Horvitz was awarded the Nobel Prize in Physiology or Medicine in 2001.

Conservation of Apoptotic Pathways

Apoptotic pathways are remarkably conserved across different species, from nematodes to mammals.

  • Key proteins involved:

    • Bcl-2 family: A group of proteins that regulate mitochondrial functions during apoptosis, playing a significant role in determining cell fate.

    • Caspases: A family of cysteine proteases that execute the cell death program by cleaving specific substrates to facilitate apoptosis.

Mechanisms of Apoptosis

Morphological Changes

Apoptosis involves specific morphological changes, including:

  • Chromatin condensation and DNA fragmentation.

  • Cell shrinkage and formation of apoptotic bodies, which are then efficiently removed by macrophages through phagocytosis.

Two-pathway Model of Apoptosis

  • Intrinsic Pathway: Triggered by internal cellular signals, such as stress and DNA damage, leading to mitochondrial changes and activation of apoptotic proteins.

  • Extrinsic Pathway: Activated through external death signals, particularly interactions between death ligands and their receptors on target cells.

Role of Bcl-2 Family in Apoptosis

Anti-apoptotic and Pro-apoptotic Functions

  • Anti-apoptotic proteins (e.g., Bcl-2, Bcl-XL): These proteins help to prevent apoptosis by maintaining mitochondrial integrity and preventing the release of apoptogenic factors.

  • Pro-apoptotic proteins (e.g., Bax, Bak): These proteins facilitate mitochondrial outer membrane permeabilization (MOMP), leading to the release of cytochrome c and apoptosis.

Regulation of Apoptosis

The balance between pro-apoptotic and anti-apoptotic signals is crucial in determining cell fate. The activation of pro-apoptotic Bcl proteins results in MOMP, leading to the release of cytochrome c from the mitochondria.

Mechanism of Cytochrome C Release

Upon release from the mitochondria, cytochrome c binds to Apaf-1, forming a complex that accelerates caspase activity, initiating the apoptosome formation, which triggers the caspase cascade and leads to cell death.

Cancer and Apoptosis

Resistance to Apoptosis in Cancer

Cancer cells often acquire resistance to apoptosis through various mechanisms:

  • Increased expression of anti-apoptotic Bcl-2 proteins, allowing them to evade programmed cell death.

  • Inactivation of key apoptotic regulators such as p53 and caspases, which normally mediate the apoptotic response.

Targeted Therapy

  • BH3 mimetics: A class of drugs designed to inhibit anti-apoptotic Bcl-2 proteins, aiming to restore apoptotic signaling in cancer cells.

  • Venetoclax: A specific BH3 mimetic that inhibits Bcl-2, promoting apoptosis in cancer cells that overexpress this protein.

Conclusion

Apoptosis is a tightly regulated process essential for maintaining cellular homeostasis and normal tissue function. Dysregulation of apoptosis contributes significantly to cancer progression, making it a critical target for therapeutic strategies in oncology.