Experimental evidence suggests a relationship between the proliferation of cancer and programmed cell death or apoptosis. Apoptosis is a homeostatic function of multi-cellular organisms that culminates in the death of redundant cells or cells whose existence could be detrimental to the organism. These cells are deemed harmful, as in many instances, the DNA molecule has mutated during the cell’s life and therefore could result in the replication of an incorrect DNA sequence or structure.
Apoptosis can be primarily induced by 2 methods: the intrinsic and extrinsic methods. The Intrinsic activation of the apoptotic transduction pathway involves the release of several proteins from the mitochondria within the cell, when receptors within the cytoplasm are activated by a broad spectrum of ‘death’ stimuli such as irreparable DNA damage, such as ionizing radiation. The proteins that are released by the mitochondria are termed nucleases and proteases. These molecules essentially 'cut up' the proteins and DNA of the cell. The extrinsic activation of the apoptotic transduction pathway involves the activation of a cell surface trans-membrane that belongs to a family of receptors known as the tumour necrosis factor (TNF) or commonly known as the ‘death receptors’. The ensuing signal transduction pathway causes the activation of the mitochondria and the subsequent release of proteins from the mitochondria that cause the death of the cell. From these apoptosis activation sequences, should a cell’s DNA become damaged or mutated it could cause a disruption in the signal transduction pathway for the apoptosis to be effective in killing the cell. This means that the damaged DNA of the cell would possibly be able to replicate, thus increasing the numbers of damaged cells. This form of uncontrolled replication as a result from damaged DNA is broadly known as cancer.
Cancer is a disease that is thought to originate from a discrepancy in the apoptosis function of a cell; meaning that the DNA of a cell has mutated in such a way that does not inhibit cellular replication as normally occurs in other cells. This results in the proliferation of mutated cells that can ultimately kill the organism. For example, it has been determined that the C.elegans Ced-4 protein in human melanoma cells is defective, which disrupts the transduction sequence of the apoptotic pathway that would normally culminate in the cell’s death. This defective protein allows the melanoma cells’ to proliferate. C.elegans Ced-4 protein is termed as a ‘death’ protein that when activated causes a transduction cascade, which results in the production of proteases and nucleases that are responsible for the destruction of proteins and DNA of a cell, culminating in cell death.
Currently, research is being conducted into rectifying the apoptosis in cancerous cells such that the cancerous cells can be eradicated without any detrimental effects for other required cells. One such research venture is into TRAIL. TRAIL (Apo2 ligand) is a death protein that essentially induces the suicide signal transduction cascade leading to cell death by an increase in the effectiveness of the pertinent executioner enzymes. TRAIL is currently in early clinical trials and is a promising anti-cancer therapy, especially as it has the potential to be lethal to chemotherapy-resistant tumours.
For more reading check out this article:
Mei Lan Tan, Jer Ping Ooi, Nawfal Ismail, Ahmed Ismail Hassan Moad,
and Tengku Sifzizul Tengku Muhammad, ‘Programmed Cell Death Pathways and Current Antitumor Targets’, 2009, Pharmaceutical Research, Vol 26, No.7, Pages 1547-1560, DOI: 10.1007/s11095-009-9895-1
Aaron Heffernan
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