Senescence is regarded as a physiological response of cells to stress, including telomere dysfunction, aberrant oncogenic activation, DNA damage, and oxidative stress. This stress response has an antagonistically pleiotropic effect to organisms: beneficial as a tumor suppressor, but detrimental by contributing to aging. The emergence of senescence as an effective tumor suppression mechanism is highlighted by recent demonstration that senescence prevents proliferation of cells at risk of neoplastic transformation. Consequently, induction of senescence is recognized as a potential treatment of cancer. Substantial evidence also suggests that senescence plays an important role in aging, particularly in aging of stem cells. In this paper, we will discuss the molecular regulation of senescence its role in cancer and aging. The potential utility of senescence in cancer therapeutics will also be discussed. 1. Introduction Senescence was first described as a state of irreversible growth arrest that normal human fibroblasts enter at the end of their replicative lifespan [1]. This phenomenon has been observed in a variety of somatic cells derived from many species, which is in contrast to the infinite replicative capacity displayed by germline, cancer, and certain stem cells [2]. Senescent cells are irreversibly arrested in G1/G0 phase of the cell cycle and lose the ability to respond to growth factors [3, 4]. They show sustained metabolic activity for long periods of time [5] and become resistant to apoptosis [6, 7]. In addition, senescent cells undergo distinctive changes in morphology to a flat and enlarged cell shape [8] and are often accompanied by the induction of acidic senescence-associated β-galactosidase (SA-β-gal) activity [9]. At the molecular level, alterations in gene expression specific to senescent cells have been identified [10–14], including those constituting senescence-associated secretome, which can trigger profound changes in the surrounding cells and microenvironment [15–17]. The changes of gene expression in senescent cells can be partially explained by alterations in chromatin structure [13], including the formation of senescence-associated heterochromatic foci (SAHF), which is associated with trimethylated lysine 9 of histone H3, heterochromatin protein 1, and high-mobility group A protein [18–20]. The formation of SAHF requires the recruitment of pRb to E2F-responsive promoters and is responsible for the stable repression of E2F target genes, possibly contributing to the irreversibility of senescence [18]. 2. Telomere-Dependent
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