Cell deaths: A new lease on life

CELLS THAT NEVER DIE CAN KILL YOU!

Cells are the tiniest form of life — the structural and functional units of all living things. The human body consists of an estimated 30-trillion cells. These cells are composed of various structures called organelles, which are built largely from proteins. Biochemical reactions in cells are guided by specialized proteins (enzymes) that speed up chemical reactions. The deoxyribonucleic acid (DNA) contains the hereditary information for cells, while the ribonucleic acid (RNA) works with DNA to build scores of proteins the cells need.

Cells are monitored by a myriad of mechanisms that keep them working in cooperation with other cells. When impairment prevents them from doing so, they either repair themselves or perish.

Death of Cells

Millions of times per second in the human body, cells perished as an essential part of the normal cycle of cellular replacement. There are two ways in which cells perish. It is either that their death might be caused by injurious agents or they are induced to commit suicide.

Death by injury

Cells can die as a result of unpredictable traumatic events, such as infection or exposure to toxic chemicals. This unplanned cell death, called “necrosis”, induces cells to undergo a characteristic series of changes. During necrosis, the cell’s outer membrane loses its ability to control the flow of liquid into and out of the cell. The cell swells up and eventually bursts, releasing its contents into the surrounding tissue. A cleanup crew composed of immune cells then moves in and mops up the mess, but the chemicals the cells use cause the surrounding tissues to become inflamed and sensitive.

Death by suicide

The intrinsic pattern of events in death by suicide is so systematic that the process is often called programmed cell death (PCD) or “apoptosis”. Apoptosis is a form of cell death necessary to make way for new cells and to destroy cells that represent a threat to the integrity of the organism. During apoptosis, the cell shrinks and pulls away from its neighboring cells. Then, it develops bubble-like blebs on its surface, with fragments breaking away and escaping like bubbles from a pot of boiling water. The DNA in the nucleus condenses and breaks into regular-sized fragments, and soon the nucleus itself, followed by the entire cell, disintegrates. A cellular cleanup crew rapidly mops up the remains.

Signaling pathways that regulate programmed cell death

Apoptosis is regulated by the integrated activity of a variety of signaling pathways, some acting to induce cell death and others acting to promote cell survival. The balance between survival and death is of such importance that the cell spends considerable energy maintaining it. There are three mechanisms by which a cell commits suicide by apoptosis.

Intrinsic pathway

Intrinsic or mitochondrial pathway is generated by signals arising within the cell. In the intrinsic pathway, DNA damage induces release of cytochrome C from the intermembrane space. The apoptotic protease activating factor 1 (APAF-1) activates caspase-9 through cleavage, and caspase-9 generates a signaling cascade of caspase cleavage that results in direct DNA fragmentation. The intrinsic pathway is antagonized by the mitochondrial anti-apoptotic proteins Bcl-2 and Bcl-xL, which inhibit the pro-apoptotic proteins Bax and Bak.

Extrinsic pathway

The extrinsic pathway, which is triggered by external signals, begins with the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptors, which causes formation of the death inducing signaling complex (DISC). Once activated, caspase-8 activates effector caspases such as caspase-3. Inhibition of the extrinsic pathway occurs through cellular Fas-associated protein with death domain-like IL-1 b-converting enzyme-inhibitory protein (cFLIP) function, which is a procaspase-8 or procaspase-10 homolog that prevents caspase-8 recruitment to the DISC.

Apoptosis-inducing factor

Apoptosis-inducing factor (AIF) is a protein that is normally located in the intermembrane space of mitochondria. AIF is caused by dangerous reactive oxygen species and does not use caspases to self-destruct. When the cell receives a signal telling it that it is time to die, AIF is released from the mitochondria, migrates into the nucleus, and binds to DNA, which triggers the destruction of the DNA and cell death.

Alternative pathways that regulate programmed cell death

Although apoptosis is the most common form of PCD, recent research has shown that cell death can also occur by alternative, non-apoptotic mechanisms.

Autophagy

Autophagic cell death does not require caspases, and rather than possessing the distinct morphological features of apoptosis, the dying cells are characterized by an accumulation of lysosomes. Autophagy recycles cell components and degrades proteins. It is stimulated by starvation, cytokine, caspase inhibition, and drug treatment.

On the other hand, the p53 (a protein of 53,000 daltons) may positively or negatively regulate autophagy. The p53 is a critical regulator of cell cycle checkpoints, senescence, and apoptosis. Hence, it is no surprise that nearly 50 percent of all human cancers harbor mutated or deleted p53. The fundamental regulation of autophagy by p53 lies in its localization: nuclear p53 leads to autophagy and autophagic cell death, while cytoplasmic p53 hinders it.

Regulated necrosis

It appears that some forms of necrosis can be programmed cellular response, rather than simply representing uncontrolled cell destruction as the result of an acute injury. In contrast to unregulated necrosis, these forms of regulated necrotic cell death are induced as a programmed response to stimuli such as infection or DNA damage. Necrosis is regulated by poly ADP-ribose polymerase 1 (PARP-1), a DNA repair protein. Hyperactivation of PARP-1 by DNA damage through alkylating agents can deplete cytosolic nicotinamide adenine dincucleotide (NAD) and trigger necrosis.

When cells achieve immortality

A normal cell has a mortality rate of about 40 to 50 cell divisions, which is controlled in part by telomeres. These protective segments at the ends of the cell’s DNA shorten with each cell division until they can no longer protect the DNA. At this point cell division severely damages the DNA, ultimately killing the cell.

Cancer cells, however, escape this protective mechanism by producing a protein called telomerase, which extends the length of telomeres indefinitely, rendering the cells immortal and capable of never-ending cell division.

Cell proliferation and tumorigenesis

Tumorigenesis is literally the creation of cancer. It is a process by which normal cells are transformed into cancer cells. When mutations build up within a cell, the cell will usually self-destruct. If this fails to occur, the cell may divide and give rise to mutated daughter cells, which continue to divide and spread, gradually forming a malignant mass called a “tumor”.

Benign tumors do not invade other tissues and are limited to one site, making surgical removal possible and the odds for a full recovery excellent. On the other hand, malignant tumors invade neighboring tissues and travel to distant sites, forming secondary growths known as “metastases”.

Role of cell death pathways in cancer therapy

Chemotherapy, the term most commonly refers to the treatment of cancer using specific drugs, is designed to destroy cancer cells by slowing or reversing the growth rate of tumors. Many of the chemotherapeutic drugs used today are cytotoxic (cell-killing) for both malignant and normal cells.

As normal cells die off, an unpleasant side effects commonly result, such as hair loss, mouth sores, nausea or vomiting, among others. These have prompted biomedical scientists to continually pursue more effective chemotherapeutic agents that specifically attack cancer cells without affecting healthy cells. Moreover, there are other approaches being developed that are designed to rescind the longevity of cancer cells. Since some forms of cancer do not respond well to cancer drugs, the approach is to target the cell death pathways to render a cancer cell once again sensitive to regulated cell death

Drugs targeting the intrinsic pathway

Many chemotherapeutic agents are currently in development that target and induce apoptosis at various stages of the intrinsic pathway, like the first class drug antisense oligonucleotides targeting anti-apoptotic genes, the second class small molecule inhibitors, and the small mitochondria-derived activator of caspases (SMAC) mimetics.

Drugs targeting the extrinsic pathway

Present therapeutic strategies targeting the extrinsic pathway are based on two primary approaches: TRAIL-receptor recombinant ligands and agonist antibodies. Recombinant human TRAIL (rhTRAIL) can trigger apoptosis in a p53-independent manner in 50 percent of cancer cell lines and has little, if any, effect on non-malignant cells. Meanwhile, the monoclonal antibodies, available for both the TRAIL-R1 and TRAIL-R2 receptors, have demonstrated increased anticancer activity and long term tumor control. These results emphasize that identifying the specific location of the defects in a cell death pathway has a profound impact on treatment.

Drugs targeting autophagy

Temozolomide is a drug that has been shown to induce autophagic cell death. Clinical trials of temozolomide, in combination with thalidomide or cisplatin, showed a modest six month progression-free survival (PFS) for cancer patients. Adding temozolomide to radiotherapy increases the median survival and the two-year survival in newly diagnosed cancer patients.

Drugs targeting necrosis

Necrosis is activated by photodynamic treatment (PDT), in which PDT selectively targets abnormal cells while preserving normal surrounding tissues. The preferential accumulation of certain photosensitizing compounds in tumor cells and the ability to treat only the defined tumor make PDT a promising therapeutic approach.

Non-drug cancer treatment

Aside from cancer drug administration, oncologists also employ the use of radiation to destroy cancer cells and use of surgery to remove tumors. Surgery and radiation are local treatments only, but they are mainly useful for attacking a specific tumor and any cancerous threat in immediately surrounding tissue.

A new lease on life

The existence of cellular defects in many cancers has contributed to an acquired resistance to apoptotic cell death, lowering the effectiveness of chemotherapy and radiotherapy. The mechanisms by which cells achieve this resistance to treatment are still being studied. Scientists believe that a more precise understanding of cancer-specific regulation of cell death may facilitate the development of the “antibiotics for cancer” in the near future.

References:

1/ http://www.exploratorium.edu

2/ http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/A/Apoptosis.html

3/ http://www.ajcr.us

4/ http://www.nigms.nih.gov

5/ http://www.wonderquest.com/CellsLifeSpan.htm

6/ http://www.nature.com/cdd/journal/v15/n9/full/cdd200891a.html

7/ http://www.dartmouth.edu/~cbbc/courses/bio4/bio4-lectures/theCell.html

**Unpublished write-up by Ludwig Ritchel A. Kalambacal for The Core Group Publishing.