Introduction to Senescence
Senescence is the a state of irreversible growth arrest that involves the permanent and irreversible arrest of the cell cycle. This process is characterized by specific morphological, physiological, and sub-cellular changes. At the morphological level, senescent cells may undergo a number of processes and they include atrophy, pigment granules accumulation and pyknosis. Physiological changes include calcium ion accumulation, ribosomal RNA loss, transcriptional reduction, protein synthesis declination, collagen stiffening, and reduced energy production. Structural changes include alterations in the fluidity and permeability of the plasma membrane, decrease in granular ER, and degeneration of mitochondria. The state of senescence was first examined by Hayflick and Moorhead (1961) based on their research on serial cultivation of human diploid cell strains (9). Based on their results, they observed that human fibroblasts underwent a state of irreversible growth arrest after sequential cultivation in vitro. On the other hand, this onset of growth restriction was unseen in cancer cells, where they were observed to be able to evade senescence and proliferate at indefinite rates (9). Many tumor suppressor genes are involved in senescence pathways (2). In cancer cells, however, senescence is not permanent. Cancer cells undergo crisis and immortalization to avoid entering a non-proliferative, senescent state. Senescence has thus been considered a potential cancer defense, especially since normal cells sometimes respond to various stresses by entering senescence. Senescence occurs in normal cells in response to a number of different mechanisms and stresses.
Replicative senescence occurs when the telomeres capping the ends of linear chromosomes become critically shortened (4). Once cells reach their Hayflick limit, a DNA damage response is triggered which then initiates cell-cycle growth arrest.
DNA damage accumulation in the cell due to UV and ionizing radiation may also induce senescence. This may be due to decline in DNA repair capacity, leading to lower overall gene expression in the cell, or to damage to mitochondrial DNA that causes less energy production. DNA damage is also able to activate genetically programmed processes that result in senescence. This may occur via expression of genes encoding hydrolytic enzymes or inhibitors of DNA synthesis. Additionally, senescence can be triggered by oxidative DNA stress, which occurs through the production of Reactive Oxygen Species (ROS), including hydrogen peroxide and superoxide ions, as a by-product of normal cellular oxygen metabolism in aerobic organisms (5). ROS are able to disrupt cell and nuclear membranes leading to changes in membrane permeability as well as damage in DNA and cellular proteins. In addition to direct DNA damage, oxidative stress also activates p16 and accelerates telomere shortening (3).
The p53 and p16-Rb pathways play important roles in senescence. In the p53 pathway, DNA damage induces either ATM/ATR and Chk1/Chk2 proteins or the ARF protein to activate p53, which then stimulates the transcriptional target p21 to cause senescence (3). p21 is itself key to senescence because it has been shown to mediate the pRB pathway as well. Reducing its activity experimentally prevented telomere-induced senescence (4). In the p16-Rb pathway DNA damage causes oncogenic RAS to stimulate p16 expression which then, in a similar mechanism to p21, induces pRB to suppress the E2F-controlled transcription of cell proliferation gene targets, thus leading to senescence (4).
A final mechanism of senescence induction is oncogene activation. Normal cells respond to many oncogenes and oncogenic stimuli by activating DNA damage pathways and entering senescence. The first observation of this process came through overexpression of oncogenic RAS and members of the RAS signaling pathway in regular human fibroblast cells (6). Oncogenes can involve increased mitogenic stimulation and lead to a loss of anti-mitogenic tumor-suppressor genes, both of which can threaten oncogenic transformation of the cells and thus elicit a defensive senescence response, known as oncogene-induced senescence (4). In this case, senescence is a tumour suppressive mechanism to protect against uncontrolled proliferation. Again, the DNA damaging actions of oncogenes like RAS largely work through the activation of p16, p53, and ARF, and can also stimulate inflammatory gene activity and chromatin condensation, two other hallmarks of senescence (6).
Cancer cells must escape or avoid senescence in order to sustain their proliferative abilities. Accordingly, the role of senescence in preventing abnormal proliferation of cancerous cells has become an increasing focus among researchers in the search for cancer therapies (4). In particular, causing cellular DNA damage and the subsequent induction of senescence in damaged cells has been extensively explored to stop proliferation of tumorigenic cells.
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