Mechanism Of Senescence Induction Research Articles

The Potential of Senescence as a Target for Developing Anticancer Therapy.

Senescence occurs in response to various stimuli. Senescence has attracted attention because of its potential use in anticancer therapy as it plays a tumor-suppressive role. It also promotes tumorigeneses and therapeutic resistance. Since senescence can induce therapeutic resistance, targeting senescence may help to overcome therapeutic resistance. This review provides the mechanisms of senescence induction and the roles of the senescence-associated secretory phenotype (SASP) in various life processes, including therapeutic resistance and tumorigenesis. The SASP exerts pro-tumorigenic or antitumorigenic effects in a context-dependent manner. This review also discusses the roles of autophagy, histone deacetylases (HDACs), and microRNAs in senescence. Many reports have suggested that targeting HDACs or miRNAs could induce senescence, which, in turn, could enhance the effects of current anticancer drugs. This review presents the view that senescence induction is a powerful method of inhibiting cancer cell proliferation.

Inhibition of NADPH Oxidases Activity by Diphenyleneiodonium Chloride as a Mechanism of Senescence Induction in Human Cancer Cells.

NADPH oxidases (NOX) are commonly expressed ROS-producing enzymes that participate in the regulation of many signaling pathways, which influence cell metabolism, survival, and proliferation. Due to their high expression in several different types of cancer it was postulated that NOX promote tumor progression, growth, and survival. Thus, the inhibition of NOX activity was considered to have therapeutic potential. One of the possible outcomes of anticancer therapy, which has recently gained much interest, is cancer cell senescence. The induction of senescence leads to prolonged inhibition of proliferation and contributes to tumor growth restriction. The aim of our studies was to investigate the influence of low, non-toxic doses of diphenyleneiodonium chloride (DPI), a potent inhibitor of flavoenzymes including NADPH oxidases, on p53-proficient and p53-deficient HCT116 human colon cancer cells and MCF-7 breast cancer cells. We demonstrated that the temporal treatment of HCT116 and MCF-7 cancer cells (both p53 wild-type) with DPI caused induction of senescence, that was correlated with decreased level of ROS and upregulation of p53/p21 proteins. On the contrary, in the case of p53−/− HCT116 cells, apoptosis was shown to be the prevailing effect of DPI treatment. Thus, our studies provided a proof that inhibiting ROS production, and by this means influencing ROS sensitive pathways, remains an alternative strategy to facilitate so called therapy-induced senescence in cancers.

TMIC-17. ASTROCYTE SENESCENCE CONTRIBUTES TO SEX DIFFERENCES IN THE AGE-RELATED INCREASE IN GLIOBLASTOMA INCIDENCE

Abstract Incidence rates for glioblastoma increase exponentially with age in a sex-specific manner, with a steeper increase observed in men. This suggests that age may be a more significant factor in promoting male tumors than female tumors. Drivers in the age-related cancer increase include both the accumulation of DNA damage and microenvironment changes, specifically an increase in the number of senescent cells. Cellular senescence comprises two distinct components – a cell cycle arrest program that prevents proliferation of mutated cells and acts as a potent anti-cancer mechanism, and a paracrine signaling component that can have both pro- and anti-tumorigenic properties. The contribution of senescence to brain tumor incidence and outcome is currently unknown; additionally, no research has been done on whether there are sex differences in mechanisms of senescence induction or in the secretory phenotype of senescent cells. Using both wildtype astrocytes and a glioblastoma model, we show that female cells have a lower threshold for senescence induction in response to oxidative stress, telomere shortening, and DNA damage, and that sex differences in senescence induction in response to DNA damage are in part mediated by differences in the regulation of p21. In addition, we show that male and female senescent astrocytes differ in their secretory phenotypes. Male senescent astrocytes secrete more tumor promoting factors, and conditioned media from male but not female senescent astrocytes promotes tumor cell proliferation. These findings provide a potential explanation for sex differences in glioblastoma incidence rates. Achieving a better understanding of mechanisms of senescence and how they differ in male and female cells could advance development of senescence directed therapies and potentially improve cancer treatment for a range of tumor types.

Abstract A16: Wnt antagonist SFRP1 functions as secreted mediator of senescence

Abstract The purpose of this study was 1) to identify the mediator(s) of senescence that are secreted from senescent cells and induce senescence in an autocrine and paracrine fashion and 2) to dissect the mechanism of senescence induction by such secreted mediator(s). Cellular senescence has emerged as critical tumor suppressive mechanism in recent years, but relatively little is known about how senescence occurs. We undertook a quantitative proteomic analysis of proteins secreted from human primary fibroblasts induced to senesce by DNA damage, Ras oncogene, or replicative telomere shortening, and determined that a number of previously reported SASP (senescence-associated secretory phenotype) factors are oversecreted in different combinations from three types of senescent cells. This analysis also identified the oversecretion of SFRP1, a secreted antagonist of Wnt signaling, upon DNA damage-induced senescence. SFRP1 is a tumor suppressor whose expression is frequently silenced by promoter methylation in various types of human cancers. SFRP1 oversecretion occurred upon treatment with different DNA damaging agents or by oxidative stress. Interestingly, nonsenescent fibroblasts acquired senescence phenotypes upon co-culture with senescent fibroblasts induced to senesce by DNA damage or by SFRP1 overexpression; this effect was alleviated by the addition of anti-SFRP1 antibodies to the culture medium. This experiment suggested that secreted SFRP1 can mediate the “spreading of senescence.” We went on to show that SFRP1 lentiviral expression or recombinant SFRP1 treatment induces senescence. Conversely, SFRP1 knockdown or addition of anti-SFRP1 antibodies to the culture medium inhibited the DNA damage-induced or oxidative stress-induced senescence in fibroblasts. The role of SFRP1 in senescence induction was also examined in epithelial cells. Upon etoposide-induced DNA damage, human primary retinal pigment epithelial (RPE) cells displayed SFRP1 oversecretion and underwent senescence. Etoposide-induced senescence of RPE cells was alleviated by SFRP1 shRNAs or by anti-SFRP1 antibody. Further, recombinant SFRP1 induced senescence in RPE cells. Recombinant SFRP1 also induced senescence in primary mammary epithelial cells and MCF-7 breast cancer cells, which lack SFRP1 expression due to promoter methylation. These results suggest that SFRP1 functions as secreted mediator of senescence in both fibroblasts and epithelial cells. Regarding the downstream pathways, we demonstrated that SFRP1 induces senescence by silencing Wnt signaling. A pharmacological inhibition of Wnt signaling or knock-down of β-catenin also resulted in senescence. Furthermore, we demonstrated the senescence-inducing activity for all five members of the SFRP family of secreted Wnt antagonists as well as DKK1, which belongs to a distinct class of secreted Wnt antagonists. SFRP1-induced or Wnt downregulation-induced senescence was accompanied by dephosphorylation of Rb and was abolished by Rb knock-down, indicating the critical importance of the Rb pathway in senescence induction. Although the primary mode of SFRP1 inactivation in tumors appears to be promoter methylation, there are also reports of cancer-associated mutations in the coding region of SFRP1. We analyzed two SFRP1 mutants found in colon cancer and glioblastoma and determined that both of these SFRP1 mutants are defective for antagonizing Wnt signaling and inducing senescence. Based on these results, we propose SFRP1 is an extracellular component of stress-induced senescence signaling that responds to potentially carcinogenic stresses such as DNA damage and oxidative insult and induces cellular senescence in an autocrine and paracrine fashion, which may lead to non-cell autonomous tumor suppression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr A16.

Mechanism of Senescence Induction by Silicone Oil

AbstractThe physiological basis for senescence symptoms induced by spraying attached primary leaves of bean plant (Phaseolus vulgaris L. cv. Brittlewax) with silicone oil emulsions was investigated. It was found that chlorophyll levels declined significantly between 24 and 48 h after spraying, whereas neither protein levels nor respiration rates were affected over a 7‐day period. Rates of photosynthesis and reducing sugar levels in silicone‐sprayed leaves were however significantly reduced after 1 and 24 h respectively. These responses were obtained using plants grown under low stress controlled environment conditions. By contrast, leaves on greenhouse plants did not senesce in response to silicone sprays. A possible mechanism of silicone oil action based on selective leaf penetration and inhibition of photosynthesis is postulated.