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

Mechanisms in Medicine

26 Oct 201204:16

Summary

TLDRApoptosis, 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.

Outlines

00:00

💀 Understanding Apoptosis and Its Role in Cancer

Apoptosis, or programmed cell death, is essential for controlling cell growth and maintaining tissue homeostasis. Its absence can lead to uncontrolled cell proliferation, a hallmark of cancer. Genetic alterations in cancer cells can result in both increased cell growth and a loss of apoptosis. In normal cells, apoptosis removes damaged cells and maintains a constant cell number in regenerating tissues, playing a crucial role in embryogenesis. On average, 50 to 70 billion cells in a human adult undergo apoptosis daily. The process is characterized by cell shrinkage, mitochondrial cytochrome C release, DNA fragmentation, and the formation of apoptotic bodies that are cleared through phagocytosis. There are two pathways that can activate apoptosis: the death receptor or extrinsic pathway, triggered by the tumor necrosis factor receptor superfamily, and the mitochondrial or intrinsic pathway, initiated by DNA damage. Both pathways activate caspases, enzymes that interact with inhibitors of apoptosis proteins (IAPs) and the bcl2 family of proteins, which have pro- and anti-apoptotic properties. Resistance to apoptosis in malignant cells can be due to the overexpression of anti-apoptotic proteins like survivin and bcl2, which are associated with poor outcomes in various cancers.

Mindmap

Keywords

💡Apoptosis

Apoptosis, also known as programmed cell death, is a natural process that helps maintain tissue homeostasis by limiting cell growth and replication. It is crucial for the removal of damaged cells and maintaining a constant number of cells in regenerating tissues. In the video, apoptosis is central to the discussion on how the absence of this mechanism could lead to uncontrolled cell growth, a hallmark of cancer.

💡Cellular Proliferation

Cellular proliferation refers to the increase in cell numbers through cell division. It is a normal process in growth and development but can become problematic when unchecked, as in cancer. The script mentions that genetic alterations in cancer cells lead to increased cellular proliferation, contributing to tumor growth.

💡Tissue Homeostasis

Tissue homeostasis is the state of stable equilibrium in tissue health and function, maintained by a balance between cell growth and cell death. The video script explains that without apoptosis, tissue homeostasis would be lost, leading to uncontrolled cell growth.

💡Cancer

Cancer is a disease characterized by the uncontrolled growth and spread of abnormal cells. The script discusses how genetic alterations in cancer cells lead to a loss of apoptosis, resulting in excessive cell growth without the normal cell death mechanisms.

💡Mitochondrial Cytochrome C Release

Mitochondrial cytochrome C release is a key event in the intrinsic pathway of apoptosis. It occurs when the mitochondria release cytochrome C into the cytoplasm, triggering a cascade of reactions that lead to cell death. The script mentions this as part of the changes that characterize apoptosis.

💡Phagocytosis

Phagocytosis is the process by which cells engulf and digest cellular debris or pathogens. In the context of apoptosis, phagocytosis is responsible for clearing the apoptotic bodies, maintaining tissue health. The script describes phagocytosis as the mechanism that clears apoptotic cells.

💡Death Receptor Pathway

The death receptor pathway, also known as the extrinsic pathway of apoptosis, is triggered by the activation of certain receptors, such as the tumor necrosis factor receptor superfamily. The script identifies this pathway as one of the two main mechanisms that can activate apoptosis.

💡Mitochondrial Pathway

The mitochondrial pathway, or intrinsic pathway of apoptosis, is initiated by factors such as DNA damage. It is one of the two pathways discussed in the script that can lead to apoptosis, emphasizing its role in response to cellular stress.

💡Caspases

Caspases are a family of enzymes that play a central role in the execution of apoptosis. They are activated by both the death receptor and mitochondrial pathways and interact with various proteins to facilitate cell death. The script highlights caspases as key enzymes in the apoptotic process.

💡Inhibitors of Apoptosis Proteins (IAP)

Inhibitors of Apoptosis Proteins, or IAPs, are a family of proteins that can inhibit or delay apoptosis. The script mentions survivin as an example of an IAP that is overexpressed in many cancers, contributing to resistance to apoptosis.

💡Bcl2 Family

The Bcl2 family of proteins includes both pro-apoptotic and anti-apoptotic members that regulate cell death. The script discusses the overexpression of anti-apoptotic Bcl2 in B cell lymphomas, which can lead to resistance to apoptosis.

💡Anti-Cancer Agents

Anti-cancer agents are substances that are used to treat cancer by targeting various aspects of cancer cell biology. The script mentions the development of agents that target anti-apoptotic molecules, such as bcl2, to reduce their levels and restore the apoptotic process in cancer cells.

💡Nuclear Factor Kappa B (NF-κB)

NF-κB is a family of transcription factors that regulate the expression of genes involved in immune responses and cell survival. The script explains that overexpression of NF-κB in tumors can lead to increased transcription of anti-apoptotic proteins, contributing to apoptotic resistance.

💡Proteasome Inhibitors

Proteasome inhibitors are a class of drugs that block the proteasome, an enzyme complex responsible for degrading proteins within cells. The script discusses bortezomib, or Velcade, as a proteasome inhibitor that has shown promise in treating multiple myeloma by reducing levels of anti-apoptotic proteins.

Highlights

Apoptosis is a critical mechanism for controlling cell growth and maintaining tissue homeostasis.

The absence of apoptosis can lead to uncontrolled cell growth and potentially cancer.

Genetic alterations in cancer cells often result in increased proliferation and loss of apoptosis.

Apoptosis in normal cells is essential for the removal of damaged cells and maintaining cell numbers in regenerating tissues.

Embryogenesis is an important process where apoptosis plays a key role.

On average, 50 to 70 billion cells in a human adult undergo apoptosis daily.

Characteristics of apoptosis include cell shrinkage, mitochondrial cytochrome C release, and DNA fragmentation.

Apoptotic bodies are cleared through phagocytosis, a process involving the fusion of vesicles with lysosomes.

There are two pathways that can activate apoptosis: the death receptor (extrinsic) and mitochondrial (intrinsic) pathways.

Caspases are enzymes stimulated by both apoptosis pathways and interact with IAP and Bcl2 family proteins.

Resistance to apoptosis in some malignant cells can be due to overexpression of anti-apoptotic proteins like survivin and Bcl2.

Anti-cancer agents targeting anti-apoptotic molecules, such as bcl2 antisense oligonucleotides, have been developed.

Activation of transcription factors like NF-kB can lead to apoptotic resistance by increasing transcription of anti-apoptotic proteins.

The ubiquitin-proteome pathway regulates the expression of transcription factors and cell cycle proteins.

Bortezomib (Velcade) is a proteasome inhibitor that has shown promising results in multiple myeloma by reducing anti-apoptotic proteins.

Certain molecules can suppress NF-kB and AP1 activation, potentially inhibiting tumor promotion.