Around 1 in 8 men are diagnosed with prostate cancer during their lifetime. As one of the most frequently reported cancers as in Western countries, prostate cancer can be a serious problem.
The progression of its initial stages depends on androgens. They inhibit cell apoptosis and increase proliferation. Unfortunately in the late stages of prostate cancer, the tumor cells may not die. This is called apoptosis-resistant androgen-independent stage. There is no therapy for it.
Therefore, it is important to understand the molecular mechanisms that are related to how this disease progresses and how cancer cells avoid apoptotic mechanisms that contribute to uncontrolled growth.
Here, you will take a closer look at the most important signaling pathways involved in prostate cancer apoptosis and cell growth, including everything that leads up to cell death.
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What Is Cell Death?
Cell death is a crucial process in the body and cell cycle. It stimulates the removal of unwanted cells. Particularly dying or dead cells that shouldn’t be in the body. If left in the system, these cells can cause countless diseases.
There are multiple forms of programmed cell death. But, apoptosis is the one researchers understand best. Multiple treatments available today act through apoptosis—for example, anti-cancer, anti-inflammatory, and non-steroidal treatments.
Future treatments are aimed at changing apoptosis. They could be used to treat various common diseases. Experts claim that apoptosis has a fundamental role to play in preventing prostate cancer.
How Do Cells Die?
There are unique ways in which cells can die. Some deaths are a part of a programmed “organized” process. Others leave zero traces of dead cells. While the rest trigger the immune system with contents from a dead cell.
Basically, cells die in two ways:
- Cellular suicide
- Injury or damage
Although cells can commit suicide, most cell death in vertebrates is settled through the mitochondrial pathway (or intrinsic pathway). That could be the result of DNA damage, anti-cancer therapy, or growth factor deprivation.
When it comes to the mechanism of apoptosis, it is also essential to mention the death receptor. It is a part of the tumor necrosis factor and establishes an efficient and rapid route to apoptosis. This receptor was once believed to induce cytotoxic signaling cascades.
To really understand cell death, you need to know what apoptosis is. Apoptosis is genetically regulated or programmed cell death. It’s also the primary mode of death of HeLa cells and plays a key role in numerous biological processes. Such as aging, illnesses, and embryonic development. An apoptosis assay can quantify and detect any cellular events.
According to the NHGRI (National Human Genome Research Institute), the body needs apoptosis. It relies on it during early development to get rid of unnecessary cells. Take frog tadpoles, for example.
They are born with a tail. But, as they grow older, they re-absorb and destroy full-body structures and experience a complete transformation. Apoptosis kills the cells from the tadpole’s tail, fins, and gills, and it matures into a frog. That’s why when they fully develop, frogs don’t keep their tail.
A 2011 review shows that apoptosis and the target genes (like the target gene of MicroRNA-21) could be a viable therapeutic option against carcinomas that express MiR-21. The problem is, cancer cells, like prostate cancer, can escape apoptosis. When that happens, the cells continue to divide. With improper cell cycle arrest, the human system can’t maintain an adequate cell balance.
How Does It Work?
There are two molecules in cell death regulation, and many proteins, like the Annexin V. You have the fas ligand and fas. The molecules form a valuable mechanism for maintaining immune homeostasis. Do have in mind that apoptosis is different from necrosis.
Apoptosis refers to cellular suicide. This cell death form prevents immune activation. Instead, it stimulates the usually dormant apoptosis protein known as caspase (commonly referred to as caspase activation). The effector caspase is responsible for dismantling the cell from the inside.
Intact and ruptured plasma membrane cells are hallmarks of apoptotic and necrotic cell death. Simply put, this cell death is an orderly process where the apoptotic bodies or contents of the cell break down and get packaged into smaller membrane packets. After which, the immune cells collect them, and the body removes them from the system.
In other words, the apoptotic cell will break into tinier packages, and other cells will engulf it. That’s why the apoptotic cell doesn’t leak and damage the body. This can happen in the liver cells as well.
Necrosis, on the other hand, is cell death by injury. The dead contents in the cells spill out and trigger inflammation. This happens if the cell dies from insufficient blood supply or toxins. There is also necroptosis, which is quite like necrosis.
In this form of cell death, the contents can also leak. However, its programmed cell death suicide is very similar to that of apoptosis. Cell death is triggered by the caspase (protein) in that dying cell. This is a typical outcome for virus-infected cells.
Viral apoptosis induction happens when one or more cells of a living organism are infected with a virus and cause cell death. But the impact of the infected cell greatly varies on the autophagy.
Autophagy is a self-preservation mechanism or the body’s way of removing the damaged cells. With it, it can regenerate healthier and newer cells. It literally activates a “self-eating” or “self-devouring” process that’s beneficial for overall health.
The goal of autophagy is to self-regulate and remove debris. It recycles and cleans at the same time. Like a “reset button” for the human body. Furthermore, it engages an adaptation and surviving response to different toxins and stressors that might affect the cells or cell membrane.
Difference Between the Intrinsic and Extrinsic Pathway
Caspase cascade is the central component of a proper apoptotic response. The apoptotic caspase usually divides into two classes: the effector caspase and the initiator caspase.
Every caspase is created in a cell as catalytically inactive zymogenes and must undergo a proteolytic activation. When the effector caspase activation does happen, it eventually leads to cell death. This response activates through a different signaling pathway.
At least two broad signaling pathways can cause apoptosis. There is the extrinsic pathway and intrinsic pathway. The extrinsic pathway starts on the outer section of the cell when circumstances in the extracellular environment decide that the cell should die.
The intrinsic pathway starts as a result of an injury inside the cell. This stress signals for caspase activation, which acts in a proteolytic cascade and dismantles and removes the damaged cell.
The activation is the one that triggers the caspase reaction. An initiator caspase splits an executioner caspase. There is basically a hierarchy in the caspase or chain reaction when it comes to degrading cellular components.
The Role of Mitochondria
Based on clinical reports, mitochondria play a key role in apoptosis activation in mammals. The Bcl-2 family, also known as the pro-survival proteins, is the protein that either inhibits or promotes apoptosis. It regulates the release of apoptotic proteins from the space between the inner and outer mitochondrial membrane.
Mitochondria is a double membrane-bound organelle present in the majority of eukaryotic organisms. Certain multicellular organisms have a shortage of mitochondria. Reports show that Mitochondrial cytochrome C has dual functions. It can control apoptosis and cellular energetic metabolism.
Once it releases into the cytosol, cytochrome C can start the activation cascade of caspases. The cytochrome C is an important peripheral protein of the inner mitochondrial membrane and works as an electron shuttle in the respiratory chain. Its activity is crucial for life.
What Happens to DNA During Apoptosis?
DNA fragmentation is a hallmark of apoptosis. Certain enzymes in the lumen of the endoplasmic reticulum are necessary for processing some of the recently synthesized proteins.
An endonuclease cleaves the DNA, which then fragments the chromatin into nucleosomal units. During chromatin condensation, apoptosis experiences a change from heterogeneous to an inert form. In fact, two independent mechanisms mediate DNA degradation.
First, there is the CAD (caspase-activated DNase). The cell-autonomously cleaves DNA into nucleosomal units inside dying cells. Secondly, when the macrophages engulf the cells, the DNA fragments keep degrading.
Remember, the whole purpose of apoptosis is to get rid of the cancerous or infected cells. When a normal cell’s DNA gets damaged, the system should detect that damage and fix it. If it’s impossible to repair the damage, the cell begins its own apoptosis. This ensures that it doesn’t pass on its faulty DNA to a healthy cell.
When Programmed Cell Death Goes Wrong
Apoptosis eliminates the unwanted cells as soon as possible. But, if that fails, the system will release self-reactive cells inside the body. These cells can attack nearby tissues and result in an autoimmune condition.
So, the immune system may not be able to shut down its response to a pathogen. According to a 2001 study, when there is a mutation in the apoptotic pathway, it could result in resistance to radiation and drugs. These mutations can help indicate chemoresistance.
Many illnesses link to abnormal cell death. Some of them are cancer and viral infection.
A cancer cell typically resists cell death, even if the patient receives anti-cancer treatment. When cell death functions properly, it can avoid viral replication and eliminate virus-infected and pre-cancerous cells.
Unfortunately, the homeostasis and development of immune cells don’t always go according to plan.
Sometimes prostate cancer cells can escape apoptosis and keep on dividing. That’s what makes it difficult for the system to maintain its cellular balance and properly functioning immune system.
Now that you know everything that is happening during apoptosis, you will better understand cell division and development.
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