Definition

Apoptosis is called cell death, normally when a cell gets damaged or infected the body removes the damaged cells. This basic mechanism is called as apoptosis. Apoptosis is normally a programmed cell death in order to maintain the organism healthy.

Evading Apoptosis

Evasion means to avoid or to escape, generally the cancer cells in order to maintain uncontrollable growth, they try to escape from the normal programmed cell death (apoptosis) of the cell.

Mechanism of Normal Apoptosis

Apoptosis is an extremely tidy process; cellular membranes are disrupted, the chromosomes are degraded, the DNA breaks up into fragments, and the dying, shrinking cell is swallowed up by a neighbouring cell or a patrolling immune cell, leaving no trace of the cellular suicide behind. The same is true for the webbing between our fingers in our early embryonic development. This includes cell shrinkage, organelle reduction, mitochondrial leakage, chromatin condensation nuclear fragmentation, cell membrane bubbling and breakage.        

Mechanism of Evading Apoptosis

In response to stressful stimuli, cells usually mount a cellular stress response to ensure survival. Under physiological conditions, such a stress response limits tissue damage. However, in cancer cells activation of pathways that favour cell survival instead of cell death under stressful conditions may contribute to tumorigenesis. In addition, this adaptive stress response promotes the development of acquired resistance, since current treatment approaches such as chemotherapy and irradiation trigger cellular stress pathways, and thus, initiate the activation of survival cascades and anti-apoptotic mechanisms. Hence, further insights into the molecular mechanisms of how cellular stress signals trigger anti-apoptotic mechanisms and how this contributes to tumour resistance to apoptotic cell death are expected to provide the basis for a rational approach for the development of new molecular targeted therapies.

There are two pathways for natural apoptosis; one is extrinsic death receptor pathway and intrinsic mitochondrial pathway. The cancer cells evade the apoptosis by blocking these pathways.

 Evasion of Death receptor pathway

Death receptors are part of the tumour necrosis factor (TNF) receptor gene super family, which comprises more than 20 proteins Death receptors involve in different biological functions, including the regulation of cell death and survival, differentiation, and immune regulation. Members of the TNF receptor family carry a characteristic cytoplasmic domain called the “death domain,” which plays a key role in transferring the death signal from the cell’s surface to intracellular signaling pathways. Signaling via death receptor can be impaired in human cancers via down regulation of receptor surface expression as part of an adaptive stress response. For example, in chemotherapy-resistant leukaemia or neuroblastoma cells, down regulation of CD95 expression was identified as a mechanism of acquired drug resistance.

In addition, anti-apoptotic proteins with a death effectors domain (DED) such as cellular FLICE-Inhibitory Protein (cFLIP) and phosphoprotein enriched in diabetes/ phosphoprotein enriched in astrocytes-15 kDa (PED/PEA-15) can be aberrantly expressed upon cellular stress [28, 29]. For example, high oxygen tension (hyperoxia) has been reported to lead to up regulation of cFLIP, which inhibited apoptosis during hyperoxia by suppressing both extrinsic and intrinsic apoptotic pathways, the latter via inhibition of Bax.

Evasion of Intrinsic Mitochondrial pathway

BH3-only proteins sense intrinsic signals to undergo apoptosis, such as DNA damage. They travel to the mitochondrial membrane and activate the pro-apoptotic proteins Bax or Bak. When activated, Bax and Bak bind, and cause mitochondrial outer membrane permeabilization (MOMP). 3This perforates the mitochondrial membrane, and induces the release of a crucial pro-apoptotic factor, cytochrome c, into the cytosol. Cytochrome c joins another pro-apoptotic factor, APAF1, to form the “apoptosome” complex, which in turn activates a series of caspases, leading to cell destruction. The cell death proteins are closely regulated by the tumour suppressor protein p53. The Bcl-2 family of proteins consists of both anti-apoptotic proteins, for example, Bcl-2, Bcl-X_L, and Mcl-1, these proteins inhibit the release of the Bax and Bak  by blocking the signals created by the BH3, thereby blocking the entire intrinsic apoptic pathway.

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