Introduction to Cancer Biology (Part 2): Loss of Apoptosis

Summary

Apoptosis, or programmed cell death, is essential for controlling cell growth and maintaining tissue homeostasis. Its absence can lead to uncontrolled cell proliferation, a key factor in cancer development. The script discusses the two main pathways of apoptosis activation: the extrinsic, triggered by tumor necrosis factor receptors, and the intrinsic, initiated by DNA damage. Both pathways involve caspases, which interact with inhibitors and proteins like the bcl2 family. Resistance to apoptosis in malignant cells can occur through overexpression of anti-apoptotic proteins, such as survivin and bcl2. Anti-cancer agents targeting these molecules and the ubiquitin-proteome pathway, which regulates cell cycle proteins, are highlighted as promising treatments for cancer.

Takeaways

• 🛡️ Apoptosis is a crucial mechanism for controlling cell growth and maintaining tissue homeostasis.
• 🚫 The absence of apoptosis can lead to uncontrolled cell growth, a key factor in the development of cancer.
• 🔄 Genetic alterations in cancer cells often result in increased cell proliferation and a loss of apoptosis.
• 🧬 Apoptosis is characterized by cell shrinkage, DNA fragmentation, and the formation of apoptotic bodies.
• 🔬 Phagocytosis is the process by which cells clear apoptotic bodies through the engulfment and recycling of cellular debris.
• 🔄 There are two pathways that activate apoptosis: the death receptor (extrinsic) pathway and the mitochondrial (intrinsic) pathway.
• 🚀 Caspases are enzymes that play a central role in both apoptosis pathways by interacting with various regulatory proteins.
• 🛡️ Resistance to apoptosis in malignant cells can be due to overexpression of anti-apoptotic proteins like survivin and bcl2.
• 🧬 Anti-sense oligonucleotides have been designed to target and reduce the translation of anti-apoptotic proteins.
• 🔄 Overexpression of transcription factors like NF-kB can lead to increased transcription of anti-apoptotic proteins, contributing to apoptotic resistance.
• 💊 Proteasome inhibitors, such as bortezomib (Velcade), have shown promise in treating multiple myeloma by inhibiting the proteasome and reducing anti-apoptotic proteins.

Q & A

What is apoptosis and why is it important for an organism?

Apoptosis, or programmed cell death, is a mechanism that organisms use to limit the growth and replication of cells. It is crucial for controlling cell growth, maintaining tissue homeostasis, and preventing diseases like cancer.

What would happen if apoptosis did not occur in an organism?

If apoptosis did not occur, there would be no way to control cell growth, leading to a loss of tissue homeostasis and potentially causing diseases such as cancer due to uncontrolled cell proliferation.

How does apoptosis play a role in cancer?

In cancer, genetic alterations in cells lead to increased cellular proliferation and growth, as well as a loss of apoptosis. This results in too much cell growth and too little cell death in malignant tissues.

What is the average number of cells that undergo apoptosis in a human adult daily?

In an average human adult, 50 to 70 billion cells undergo apoptosis per day.

What are the characteristics of apoptosis in normal cells?

Apoptosis in normal cells is characterized by cell shrinkage, mitochondrial cytochrome C release, fragmentation of cell DNA into multiples of 180 base pairs, and the ultimate breakage of cells into small apoptotic bodies that are cleared through phagocytosis.

What is phagocytosis and how does it relate to apoptosis?

Phagocytosis is a process where cells take in cell fragments or microorganisms in membrane-bound vesicles. The vesicles fuse with lysosomes containing proteases, and the engulfed material is processed for recycling. This process is essential for clearing apoptotic bodies.

What are the two pathways that can activate apoptosis?

The two pathways that can activate apoptosis are the death receptor or extrinsic pathway, triggered by activation of members of the tumor necrosis factor receptor superfamily, and the mitochondrial or intrinsic pathway, initiated by DNA damage.

What are caspases and what role do they play in apoptosis?

Caspases are a set of enzymes that are stimulated by both the extrinsic and intrinsic pathways of apoptosis. They interact with Inhibitors of Apoptosis proteins (IAPs) and the Bcl2 family of proteins, which have either pro- or anti-apoptotic properties.

Why do some malignant cells show resistance to apoptosis?

Some malignant cells show resistance to apoptosis due to the overexpression of anti-apoptotic proteins, such as survivin, an IAP found in many cancers, and Bcl2, which is overexpressed in B cell lymphomas due to gene translocation.

How have anti-cancer agents been developed to target anti-apoptotic molecules?

Anti-cancer agents have been developed by designing short segments of DNA complementary to the RNA of anti-apoptotic proteins like Bcl2, known as anti-sense oligonucleotides, to reduce the translation of these proteins and inhibit their anti-apoptotic effects.

What is the role of the ubiquitin-proteome pathway in regulating apoptosis?

The ubiquitin-proteome pathway regulates the expression of transcription factors and other cell cycle proteins. Certain molecules can suppress or reduce NF-kB and AP1 activation, inhibiting tumor promotion. An example is bortezomib (Velcade), a proteasome inhibitor that has shown promising results in multiple myeloma by inhibiting the proteasome, leading to increased levels of the NF-kB inhibitor and therefore less anti-apoptotic proteins.