Evading apoptosis in cancer

Carcinogenesis is a mechanistically complex and variable process with a plethora of underlying genetic causes. Cancer development consists of a multitude of steps that occur progressively starting with initial driver mutation(s), to tumorigenesis, and ultimately metastasis. During these transitions, cancer cells accumulate a series of genetic alterations that confer upon the cells an unwarranted survival and proliferative advantage. During the course of development, however, cancer cells also encounter a physiologically ubiquitous cellular program that aims to eliminate damaged or abnormal cells: Apoptosis. Thus, it is essential that cancer cells acquire instruments to circumvent programmed cell death. Here we discuss emerging evidence indicating how cancer cells adopt various strategies to override apoptosis including amplifying the anti-apoptotic machinery, downregulating the pro-apoptotic program, or both.

Roles of Apoptosis and Cellular Senescence in Cancer and Aging.

Cancer and aging are two similar processes representing the final outcome of timedependent accumulation of various irreversible dysfunctions, mainly caused by stress-induced DNA and cellular damages. Apoptosis and senescence are two types of cellular response to damages that are altered in both cancer and aging, albeit through different mechanisms. Carcinogenesis is associated with a progressive reduction in the ability of the cells to trigger apoptosis and senescence. In contrast, in aging tissues, there is an increased accumulation of senescent cells, and the nature of apoptosis deregulation varies depending on the tissue. Thus, the prevailing model suggests that apoptosis and cellular senescence function as two essential tumor-suppressor mechanisms, ensuring the health of the individual during early and reproductive stages of life, but become detrimental and promote aging later in life. The recent discovery that various anticancer agents, including canonical inducers of apoptosis, act also as inducers of cellular senescence indicates that pro-senescence strategies may have applications in cancer prevention therapy. Therefore, dissection of the mechanisms mediating the delicate balance between apoptosis and cellular senescence will be beneficial in the therapeutic exploitation of both processes in the development of future anticancer and anti-aging strategies, including minimizing the side effects of such strategies. Here, we provide an overview of the roles of apoptosis and cellular senescence in cancer and aging.

Cellular senescence (CS) is initially defined as an irreversible growth arrest of normal somatic cells, and has been proposed to contribute to tissue and organismal aging itself, and to be an intrinsic safeguard against tumor progression (1). SCs have been shown to have diverse phenotypes, including cellular flattening and hypertrophy, senescence-associated β-galactosidase activity (SAβG), senescence-associated secretory phenotype (SASP), resistance to apoptotic cell death, alterations in nuclear structure and senescence-associated heterochromatic foci (SAHF), mitochondrial expansion, and signaling events, including upregulation of cell cycle inhibitors and -pro-survival effectors (2). SCs accumulated in various tissues in mice with age, and comprised 5–40% of the total cells, depending on the tissue types (3). Although their number are relatively small in tissues, SCs can cause extensive dysfunction of the microenvironment and damage to surrounding cells and tissues, due to their pro-inflammatory senescence-associated secretory phenotype (SASP). Accumulating evidence suggests that CS plays an important role in diverse biological processes, such as embryonic development, diabetes, host immunity, wound healing, tissue renewal, as well as fibrosis, cardiovascular diseases, and cancer (4).

Since aging is one of major risk factors of human diseases, a variety of aging interventions have been developed to extend health span and to prevent or treat ARDs in in vitro and in vivoexperimental models. Caloric restriction (CR) is the only intervention shown to increase health span as well as to decrease the risk of ARDs in nonhuman primates (5). Recently, clinical trials of CR in non-obese humans revealed that a 15% lower calorie intake for 2 years delayed metabolism accompanied by reduced oxidative damage, suggesting that CR could also slow down the aging process in humans (6). Although CR can enhance healthy aging, the inconvenience of most subjects to maintain CR for a longtime limits its application. Therefore, caloric restriction mimetics (7), and calorie restriction diets or fasting-mimicking diets (8) have been proposed as alternatives. Elucidation of the mechanisms by which aging is regulated also suggested a variety of compounds and medicines, including sirtuin activators (9), AMP dependent protein kinase (AMPK) activators (10), mammalian target of rapamycin (mTOR) inhibitors (11), autophagy activators (12), that might be applicable for use in aging intervention. In addition, the use of geroprotectors, compounds and medicines that slow down aging, and thus lengthen the lifespan of model organisms has also been proposed (13). In present, a curated database of geroprotectors is available, and includes 259 compounds in 13 animal models from yeast to human, obtained from 2,408 literature (http://geroprotectors.org/). An old story tells the rejuvenation effects of young blood. Heterochronic parabiosis, in which an aged mouse and a young one were joined surgically, revealed that some factors in young blood, such as growth differentiation factor 11 with controversial reports and oxytocin enhanced tissue regeneration, and led to improvement of aging phenotypes (14). Similarly, transfusion of young serum also retarded age-related impairments in cognitive function and synaptic plasticity in aged mice (15, 16).

Although CS is one of hallmarks of aging (17), and accumulation of SCs with age has been suggested to be associated with aging and ARDs (18), direct evidence of a causal relationship between CS and aging or ARDs has only recently been validated in rodent models. Furthermore, senotherapeutics, have been implicated as novel strategies for aging intervention in applications designed to extend healthy aging and to prevent or treat ARDs.