Apoptosis and Cancer: 2020 Cancer Cells Treatment

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Medically reviewed by Victor Nguyen, PharmD

Apoptosis and Cancer

What if human cancer cells do not undergo apoptosis, but just continue to grow and divide? Although we often think that living forever might be great, it is not great when it occurs in your cells. When the damaged cells do no longer undergo normal apoptosis and divide continuously, this can be associated with the development of cancer

Apoptosis and cancer[1] are connected in some aspects. First, tumors cannot grow if the system’s normal security within the body detects and actively self-destructs. Cancers often block the mechanisms by which the body marks the growth of uncontrolled tissue for apoptosis. Second, cancer cells inactivate the genes encoding the proteins necessary to destroy malignant cells in some organ cancers like lung cancer, liver cancer, or pancreatic cancer.

Even though many things go wrong to turn a new cell to be a cancer cell, one of the most essentials is the deregulation[2] of the process of apoptosis. Cancer can occur when tumor cell division becomes out of control and the mechanisms that regulate apoptosis stop working. The tumor cells divide unexpectedly, invade, and cause the displacement of normal healthy tissues and organs.

The Apoptosis Pathway

Apoptosis[3] is triggered by various agents, including endogenous cytokines, therapeutic drugs, and cytotoxic T lymphocytes. Initiation and implementation are mediated, in many cases, by activation of proteases known as caspases

If the cells are damaged, the process of apoptosis can help to prevent them from becoming harmful to the body as a whole. Cells with DNA damage, for example, can become cancerous – apoptosis is one way to prevent that from happening.

Apoptosis happens through two different pathways[4]. The first is called the extrinsic pathway of apoptosis or death receptor pathway, which involves the killing of tumor cells initiated by cytotoxic T lymphocytes.

The other major signaling pathway leading to apoptosis is the mitochondrial or intrinsic apoptotic pathway. This pathway is regulated by the BCL 2 family proteins[5], which can affect the mitochondria. BAX and BAK are BCL 2 family proteins inducing cell death by creating holes[6] in the outer mitochondrial membrane. Mitochondrial proteins then come out in the cytoplasm where they activate caspases, leading to eventual cell death.

apoptosis and cancer

Intrinsic Mitochondrial Apoptosis Pathway

Intrinsic mitochondrial apoptosis[7] activates when the cell is stressed by a number of possible of factors, such as DNA damage, exposure to UV light and X-rays, hypoxia, accumulation of misfolded proteins within the cell, and chemotherapeutic agents. When the cell is stressed, the intermembrane space of the mitochondria[8] leaks cytochrome c into the cytosol, leading to activation of caspase 9. TP53 and Bcl-2 family genes regulate this pathway.

Extrinsic or Death Receptor Pathway

The extrinsic pathway[9] is triggered when the cell perceives the death of the other cell signal. This pathway is linked to receptors other related ligands that induce apoptosis, which bind to receptors on the cell surface, leading to activation of the apoptosis pathway. As a result of binding, this involves the creation of a “death-inducing signaling complex” (DISC) and the activation of auto-catalytic procaspase-8. When caspase-8 is activated, the execution or terminal phase is triggered. The following are two pathways that both lead to caspase-8 activation.

  • TNFR is activated by TNF cytokines[10]: TNF-alpha is a cytokine that originated from the primary mediator of extrinsic apoptosis called macrophages. Tumor necrosis factor (TNF-alpha) binds to receptors TNFR1, leads to caspase activation.
  • Fas (CD95) receptor activated by FasL[11] (Fas ligand): The Fas receptor is a transmembrane protein of the TNF family that binds Fas ligand (FasL). The interaction between FasL and Fas receptor L leads to caspase activation.

Role of cytochrome C and genetic regulation of mitochondrial apoptosis

When the cell is stressed out from the inside, this indicates a role for the  Bcl-2 protein that regulates the permeability of mitochondria in response to apoptotic signals — this protein causes the release of cytochrome c[12].

TP53 Suppressor Gene

This gene encodes a p53 protein [13] that controls the cell cycle death and is considered to be a tumor suppressor gene. If the DNA is damaged by, for example, chemotherapy agents, hypoxia, or ionizing radiation, then the TP53 gene stops the cell in the G1 phase of the cell cycle [14] and prevents further cellular proliferation. But if DNA damage is too large it will promote cells by activating the apoptotic gene BAX. The BCL 2 products of the BAX gene then turn off the anti-apoptotic genes.[15] 

Bcl-2 (b-cell lymphoma) Gene family

Located on chromosome 18 are the anti-apoptotic genes which produce Bcl-2 [16] protein expression. To prevent the release of c cytochrome, Bcl-2 proteins confine to prohibit Apaf-1. Cytochrome c is present between the outer and inner mitochondrial membranes. Once Apaf-1 is released it binds and activates procaspase 9.[17]

Perforin/granzyme

In a few instances, initiation of apoptosis can trigger by immune cells known as cytotoxic T cells. This can occur when lymphocytes secrete a protein called perforin as well as granules specialized enzymes. Perforin[18] holes targeted cells from the plasma membrane. Granules use these holes to enter the cell. After entering the cell, they release their enzymes (granzymes A and B)[19]causing a cytotoxic reaction which leads to cell death.

The Role Of Apoptosis In Cancer Cell

Apoptosis also plays a role in the progression of cancer. For a cancer cell to move to another part of the body (metastasize) should be able to survive in the blood or lymph systems and invade foreign tissue. Apoptosis normally could prevent these things.

Through further investigation, it has been concluded that besides being a regulated form of cell death, apoptosis plays a vital role in controlling the cell populations. The inability of cells to undergo this process can have dramatic consequences depending on the cell type.

Today, apoptosis is known to play an essential role, such as:

  • Maintaining a particular number of cells in an organism – With mitosis providing more than 100,000 cells within the human body every second, other cells die by apoptosis, thereby keeping a constant variety of cells present inside the body.
  • Homeostasis[20] TheB cells and T cells of the immune system and the intestinal epithelium are produced in large quantities. In the case of B and T cells, 95 percent during maturation by apoptosis. Here, apoptosis plays an important role in the control and balance of the cells to prevent autoimmunity.
  • Get rid of redundant and damaged cells. In the body, cells damaged significantly that cannot be repaired are eliminated through apoptosis. This also happens to the infected cells and autoreactive immune cells.

A New Potential Cancer Therapy

The Weizmann Institute of Science and the Hebrew University of Jerusalem developed an advanced way to cause apoptosis which may result in new approaches.

This study provides the examination of interaction among important proteins involved in cell death, mitochondrial carrier a pair of counterparts (MTCH2), and truncated BID (tBID), which are both involved in the process of apoptosis. Discovered in the laboratory of Prof.Gross.

According to their research, two proteins are an important step in starting apoptosis by binding each other. After their discovery, they develop a short protein fragment or peptides, which prevent binding each other and mimic regions of the protein. Researchers also conducted cell cultures derived from humans through experimentation resulting in cancer cell death.

“These protein segments could be the basis for future therapies against cancer cells where the natural cell death mechanism is not working properly,” said Professor Friedler. In developing anti-cancer drugs, they appear to find a remarkable correlation between those proteins that are important through activation of apoptosis through preventing its regulation.

Targeting apoptosis in cancer treatment

Tumor cell death[21] initiated by commonly-used cancer therapy such as chemotherapy, γ-radiation, immunotherapy, or gene therapy is predominantly mediated by the activation of apoptosis, the intrinsic suicide pathway of the cell. Therefore, defects in apoptosis pathways can lead to resistance to cancer therapies with current treatment approaches. Understanding the molecular mechanisms that regulate cell death programs can provide new opportunities for the development of cancer drugs.

Cancer treatment such as chemotherapy or radiotherapy forces a cancer cell to undergo apoptosis, triggering cell death. Moreover, many drugs that induce apoptosis are currently being investigated[22], and some clinical trials are as well. In addition, pro-apoptotic BH3 proteins may accumulate in cancer cells, but do not exert effects strong enough to overcome excess Bcl-2 anti-apoptotic proteins.

Currently, some clinical trials investigated drugs that may induce apoptosis. In addition, other proteins may accumulate in cancer cells such as pro-apoptotic BH3, while others do not have enough strong effect to survive against excess Bcl-2 anti-apoptotic proteins. 

The BH3 proteins can give an additional boost to strengthen the death signal from death-causing apoptosis and stimulating the intrinsic path when they mimic drugs. Potential Agents being tested directly target the anti-apoptotic protein Bcl-2 family, or even pro-apoptotic factors such as caspases or p53 protein function.

On the other hand, there are numerous approaches that drugs can target in most cancer cells that may prevent apoptosis to restore apoptotic pathways. While some cancer cells end up being resistant and accumulate new mutations.

For example, if a drug inhibits certain proteins of the Bcl-2 family, it will initiate apoptosis in normal cancer cells, as well as cancer stem cells. But if that cancer cell then acquires a mutation that upregulates caspase inhibition, the drug will be less effective.

Frequently Asked Questions

What is apoptosis?

Apoptosis is programmed (to maintain normalcy in the organism) cell death. Apoptosis is controlled so that the cells which are not needed or are potentially harmful are eliminated.

What is the cause of apoptosis in cancer?

It is caused by caspase 3, a proteolytic enzyme that causes cell death by cleaving a certain type of protein in the nucleus and cytoplasm. These caspases exist in all types of cells as an active process, which is normally activated by other caspases, producing proteolytic caspase 3 cascades. Activation triggered by an adapter protein[23]that carries several copies of a particular process is also known as the initiator. Apoptosis can also be caused by the activation of procaspase aggregation in the cell.

Event in cancer that occurs during apoptosis?

There are three apoptotic pathways in these cells — i.e. the extrinsic pathway, the intrinsic pathway, and Perforin / Granzyme Pathway.

How apoptosis is associated with cancer cells?

Apoptosis is the programmed cell death process; it is a highly regulated process. Adverse biochemical changes in the cell signal the beginning of apoptosis: once a cell enters this mode, you cannot return to its normal state. Cell death is achieved by activating protease enzymes. Each mutation that disrupts the cell signaling system that leads to the initiation of apoptosis, allows the cells to continue the unwanted changes. Thus the cells avoid death, dividing uncontrollably and possibly forming neoplasms.

What are programmed cell death apoptosis examples?

They are activated by the presence of certain antigens. Activation of the T cells may lead to the secretion and release of cytotoxic granules consisting of perforin granzyme and.

Is cell apoptosis the same as autolysis?

Apoptosis is programmed cell death, while autolysis is then digestion of the cell from the inside. Autolysis is a response to injury or infection, and generally does not occur in healthy cells, while Apoptosis can be a process in healthy tissue.


+ 23 sources

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