Apoptosis is described as a progression of organized perturbations to the cell engineering that contribute not exclusively to cellular death, but additionally prepare cells for evacuation by phagocytes. Apoptotic cell demise is orchestrated by specific individual members from the caspase group of cysteine proteases. Caspases are found to be targeting a vast number of proteins for a limited proteolysis period during this perplexing system of cell destruction.
There have been various caspase substrates that have been associated to the explicit morphological elements of apoptosis. There are also many proteins that have been designated by caspases that are known to result in cell death, even though most of these proteins are found to display minimal impact on phenotypic changes that are observed during these complex interactions.
Since proteins associated with different cell functions are broken down by caspases. It is evidently apparent that these proteins employ a process of gradual but inevitable demise system approach that will eventually lead to cell death. All in all, this elaborate demise by the caspase enactment process can be described as outcomes from numerous possibly deadly wounds as opposed to a solitary lethal blow.
Apoptosis pathways and early markers
There are two significant apoptosis pathways that have extensively been studied.
- Intrinsic pathway: This can be described by the cell receiving a signal from within itself that most often involves its own gene or protein, in this case it might be a form of a protection mechanism. There are many different types of damage and stress which can result in triggering apoptosis for example: oxygen deprivation, stress that prevents certain cell functioning normally and damage to own DNA. In these extreme cases, the cell decides that it might be too costly or dangerous to the whole organism if it continued its existence.
- Extrinsic pathway: This can be described by the cell receiving signals from other cells from different parts of the organism to initiate the process of apoptosis. This again will be a form of a protective mechanism that will benefit the organism at the expensive of an individual cell. In majority of cases the cell is either diseased, damaged or no longer required.
The main regulator for this intrinsic pathway is Bcl-2 family of proteins and this process predominantly occurs within the mitochondria. One of the key stages in this process is the permeabilization of the outer membrane. This is essential to allow the proteins to be released, activation of various caspases and the eventual occurrence of cell apoptosis. In summary, cytochrome C is released, this cytochrome C can attach to APAF-1 and this leads to activating caspase-9. The activated caspase-9 can activate caspase 3 and caspase 7 and following this elaborate cascade of events eventually results in apoptosis.
Same as many other pathways, the extrinsic pathway is an elaborate cascade of events that eventually results in apoptosis. The first step involves the binding of signal molecules to the external receptors that are present of the cell membrane. Two of the most well know signaling molecules are FAS and TRAIL. These are present in adjoining cells and are secreted if a cell is no longer required or is damaged and can be potentially harmful in the future. The receptors that bind these molecules are called FASR (FAS receptor) and TRAILR (TRAIL receptor). Following the binding process there is a confirmation change in the intracellular domain of the receptors. This causes receptor oligomerization and the recruitment of two adaptor proteins that are called FADD (FAS associated death protein) and RIPK1 (serine/threonine protein kinase 1), this interaction triggers DISC (death signaling complex).
The activated FADD interacts with pro-caspase-8 and pro-caspase-10 to cleave and break off the portion that is responsible for keeping caspase molecules inactive. Active caspase 8 and caspase 10 are formed, these are released into the cytoplasm where they can trigger changes to various molecules and messengers that are responsible for initiating DNA breakdown. Some useful biomarkers for extrinsic pathway include: Annexin V (can be used with propidium to differentiate normal cells from dead cells during early phase of apoptosis), caspase-3 and caspase-7 (regarded as effector caspases, that control various phenotypic changes that occur during the process of apoptosis for example: DNA fragmentation and membrane blistering).
Both these two pathways lead to the induction of cell death using an extensive process of activating many different types of caspases. Essentially, there are two categories of caspases: executioner caspases (these function in cleaving many target proteins and DNA fragments, this helps in the process of removal of apoptotic bodies) and inhibitor caspases (these have an important role as a therapeutic tool in the treatment of many different types of death associated pathologies). The final procedure involved during apoptosis is when proteins and organelles are packaged into a membrane bound structure that is either removed or consumed by a phagocytic process.
Apoptosis and link to cancer
Apoptosis is a fundamental adaption that is designed to lead to an organism destroying its own cells. This may seem an odd phenomenon, however, they are many benefits to this process happening. There are many roles for apoptosis and majority of the times it is during the early stages of development. It is vital in helping the body to eliminate cells that have been damaged beyond repair. It can be used to remove any unwanted cells. Most importantly, it can help to prevent the development of cancer (for example: liver cancer, breast cancer, ovarian cancer, colorectal cancer, during the process of wound healing, HIV and many birth defects). In some cases, where apoptosis is prevented from happening, this results in cell division being uncontrolled and tumors or cancer forming.
Apoptosis is vital in killing pre-cancerous cells (early signs to look out for could be the presence of infections, inflammation, benign tumors and a weak immune system). This is highlighted by the fact that individuals that contain mutations which prevent the correct functioning of apoptosis are found to have a greater chance of developing cancer. However, there are instances where increased levels of apoptosis is also found to occur in normal healthy cells, this can lead to conditions that are referred to as neurodegenerative diseases. Here cells are being destroyed when they are not supposed to be. The most common examples of these diseases include Parkinson’s disease, Lou Gehrig’s disease and Alzheimer’s disease.
The field of cancer medicine within the United Kingdom (UK), especially studies undertaken within Cancer Research UK has identified that the number of cancer cases is increasing at an alarming rate as each year passes by. In 2019, there were over 500,000 different types of cancers that are registered. This is equivalent to more than 950 new cases being diagnosed each day during 2019. Some of the most common cases identified are: breast (22.5%), lung (21.2%), prostate (19.2%) and colorectal (15.2%). Cancer is regarded mainly as a disease that affects older people, usually adults that are over the age of 65. There were over 68% of cancer that were registered in 2019 that accounted for over 65.
There needs to be more cancer screening programs, a better preventative healthcare system, development of novel chemotherapy treatments, immunotherapy procedures, a better understanding of the chemistry of cancer, better communication between patient and doctor.
There is also evidence to indicate that apoptosis plays an important function in atrophy of the muscles. This is when the body decides that spending more calories on maintenance of muscles is no longer required, especially for the muscles that are no longer being used regularly.
Many scientists view cancer as being defined as evading apoptosis. This is illustrated by the fact that apoptosis is the opposite of cell growth and cancer is described as uncontrollable cell growth. The major point being here is that cancer cells have hijacked controlled normal cell growth and they have also evaded cell death (apoptosis). This is evident by the fact that all cancer cell types have the characteristics of acquired resistance to cell death.
Cancer cells are defined as consisting of several mutation that leads to them being able to ignore normal cell signal regulation for growth and proliferation. As a result of these mutations these cancer cells can undergo uncontrolled growth and proliferation when compared to normal cells. This situation is totally different to damaged cells that will undergo apoptosis under normal circumstances, whereas in the case for cancer cells that contain specific mutations that lead to them unable to undergo apoptosis. Cancer cells continue growing and proliferating with no regulation control check points being present, this will consequently lead to the progression of many diseases which in some cases will result in tumors being formed.
Many scientists are focusing on understanding how cancer cells are regulating apoptosis, since this will be a key factor in the development of new treatments for various diseases. Many different types of studies involving cell culture, biomaterials, synthetic biology, antibody-drug conjugate, antigens, nucleic acids, statistics, pharmacology, survival training, development of novel chemotherapy treatments, cytokines, tissue biology, flow cytometry, toxicity and histogenesis have been undertaken to learn and develop a better understanding of cancers and how they are regulated.
A classical example is Alzheimer’s and Parkinson’s disease (both are neurodegenerative diseases), it is thought apoptosis is responsible for majority of cell death and the subsequent neurons that are being lost progressively.
There is more research that needs to be undertaken to better our understanding of how apoptosis pathways work in diseases or cancers. This vital information might provide valuable answers to making new breakthroughs and developing novel cancer treatment drugs.
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