Systemic induction of senescence in young mice after single heterochronic blood exchange.

Ageing is the largest risk factor for many chronic diseases. Studies of heterochronic parabiosis, substantiated by blood exchange and old plasma dilution, show that old-age-related factors are systemically propagated and have pro-geronic effects in young mice. However, the underlying mechanisms how bloodborne factors promote ageing remain largely unknown.

The senescence-associated secretory phenotype: Fueling a wound that never heals.

Wound healing is impaired with advanced age and certain chronic conditions, such as diabetes and obesity. Moreover, common cancer treatments, including chemotherapy and radiation, can cause unintended tissue damage and impair wound healing. Available wound care treatments are not always effective, as some wounds fail to heal or recur after treatment.

Oxylipin biosynthesis reinforces cellular senescence and allows detection of senolysis.

Cellular senescence is a stress or damage response that causes a permanent proliferative arrest and secretion of numerous factors with potent biological activities. This senescence-associated secretory phenotype (SASP) has been characterized largely for secreted proteins that participate in embryogenesis, wound healing, inflammation, and many age-related pathologies. By contrast, lipid components of the SASP are understudied.

Cellular Senescence and the Senescence-Associated Secretory Phenotype as Drivers of Skin Photoaging.

Chronic exposure to UVR is known to disrupt tissue homeostasis, accelerate the onset of age-related phenotypes, and increase the risk for skin cancer-a phenomenon defined as photoaging. In this paper, we review the current knowledge on how UV exposure causes cells to prematurely enter cellular senescence. We describe the mechanisms contributing to the accumulation of senescent cells in the skin and how the persistence of cellular senescence can promote impaired regenerative capacity, chronic inflammation, and tumorigenesis associated with photoaging.

Cellular Senescence Promotes Skin Carcinogenesis through p38MAPK and p44/42MAPK Signaling.

Cellular senescence entails an irreversible growth arrest that evolved in part to prevent cancer. Paradoxically, senescent cells secrete proinflammatory and growth-stimulatory molecules, termed the senescence-associated secretory phenotype (SASP), which is correlated with cancer cell proliferation in culture and xenograft models. However, at what tumor stage and how senescence and the SASP act on endogenous tumor growth is unknown.

Astrocyte senescence promotes glutamate toxicity in cortical neurons.

Neurodegeneration is a major age-related pathology. Cognitive decline is characteristic of patients with Alzheimer's and related dementias and cancer patients after chemo- or radio-therapies. A recently emerged driver of these and other age-related pathologies is cellular senescence, a cell fate that entails a permanent cell cycle arrest and pro-inflammatory senescence-associated secretory phenotype (SASP).

Secretion of leukotrienes by senescent lung fibroblasts promotes pulmonary fibrosis.

Accumulation of senescent cells is associated with the progression of pulmonary fibrosis, but mechanisms accounting for this linkage are not well understood. To explore this issue, we investigated whether a class of biologically active profibrotic lipids, the leukotrienes (LT), is part of the senescence-associated secretory phenotype. The analysis of conditioned medium (CM), lipid extracts, and gene expression of LT biosynthesis enzymes revealed that senescent cells secreted LT, regardless of the origin of the cells or the modality of senescence induction.

SILAC Analysis Reveals Increased Secretion of Hemostasis-Related Factors by Senescent Cells.

Cellular senescence irreversibly arrests cell proliferation, accompanied by a multi-component senescence-associated secretory phenotype (SASP) that participates in several age-related diseases. Using stable isotope labeling with amino acids (SILACs) and cultured cells, we identify 343 SASP proteins that senescent human fibroblasts secrete at 2-fold or higher levels compared with quiescent cell counterparts. Bioinformatic analysis reveals that 44 of these proteins participate in hemostasis, a process not previously linked with cellular senescence.

Small-molecule MDM2 antagonists attenuate the senescence-associated secretory phenotype.

Processes that have been linked to aging and cancer include an inflammatory milieu driven by senescent cells. Senescent cells lose the ability to divide, essentially irreversibly, and secrete numerous proteases, cytokines and growth factors, termed the senescence-associated secretory phenotype (SASP). Senescent cells that lack p53 tumor suppressor function show an exaggerated SASP, suggesting the SASP is negatively controlled by p53.

Oncogenic senescence: a multi-functional perspective.

Cellular senescence is defined as an irreversible growth arrest with the acquisition of a distinctive secretome. The growth arrest is a potent anticancer mechanism whereas the secretome facilitates wound healing, tissue repair, and development. The senescence response has also become increasingly recognized as an important contributor to aging and age-related diseases, including cancer.

Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse.

Unlabelled: Cellular senescence suppresses cancer by irreversibly arresting cell proliferation. Senescent cells acquire a proinflammatory senescence-associated secretory phenotype. Many genotoxic chemotherapies target proliferating cells nonspecifically, often with adverse reactions.

Crosstalk between the vitamin D receptor (VDR) and miR-214 in regulating SuFu, a hedgehog pathway inhibitor in breast cancer cells.

The vitamin D receptor (VDR), and its ligand 1α,25-dihydroxyvitamin D (1,25D) prevent breast cancer development and progression, yet the molecular mechanisms governing this are unclear. MicroRNAs (miRNAs) on the other hand, promote or inhibit breast cancer growth. To understand how VDR regulates miRNAs, we compared miRNA expression of wild-type (WT) and VDR knockout (VDRKO) breast cancer cells by a Mouse Breast Cancer miRNA PCR array.

Context-dependent effects of cellular senescence in cancer development.

Cellular senescence is an established tumour-suppressive mechanism that prevents the proliferation of premalignant cells. However, several lines of evidence show that senescent cells, which often persist in vivo, can also promote tumour progression in addition to other age-related pathologies via the senescence-associated secretory phenotype (SASP). Moreover, new insights suggest the SASP can facilitate tissue repair.

Deguelin action involves c-Met and EGFR signaling pathways in triple negative breast cancer cells.

Background: Treatment of breast cancer patients with antiestrogens and aromatase inhibitor(s) or Herceptin have shown significant success in steroid receptor positive or Her-2+ breast cancers respectively. However, choice of treatments for breast cancer patients with negative status for estrogen, progesterone receptors and HER2/neu is limited. As a result, search for appropriate therapy regimen for these triple negative breast cancers (TNBC) has become a major focus of investigations for many laboratories.

Efficacy and mechanism of action of Deguelin in suppressing metastasis of 4T1 cells.

Cancer related deaths in breast cancer patients are due to metastasis of the disease. Murine 4T1 cells (Murine mammary cancer cell line developed from 6-thioguanine resistant tumor) provide an excellent research tool for metastasis related studies because these cells are highly aggressive and readily metastasize to the lungs. In this study we determined the effect of Deguelin on in vivo/vitro growth and metastasis of 4T1 cells.

Vitamin D and breast cancer: emerging concepts.

The benefit of vitamin D in cancer prevention and to certain extent therapy has been well recognized. The active form of vitamin D, 1,25-dihydroxycholecalciferol (1,25(OH)2 D3) is a natural ligand for vitamin D receptor (VDR). Since 1,25(OH)2D3 exerts toxic effects at a concentration that is beneficial, nearly 1500 analogs of vitamin D have been synthesized and evaluated for their efficacy in a variety of carcinogenesis and human cancer models both in vitro and in vivo.

PPARγ antagonist GW9662 induces functional estrogen receptor in mouse mammary organ culture: potential translational significance.

The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) plays a central role in regulating metabolism, including interaction with the estrogen receptor-α (ERα). Significantly, PPARγ activity can be modulated by small molecules to control cancer both in vitro and in vivo (Yin et al., Cancer Res 69:687-694, 2009).

Efficacy and mechanism of action of Proellex, an antiprogestin in aromatase overexpressing and Letrozole resistant T47D breast cancer cells.

Aromatase inhibitors (AI) are considered as a first line therapy for ER+PR+ breast cancers. However, many patients acquire resistance to AI. In this study, we determined the response of antiprogestin CDB-4124 (Proellex) on the aromatase overexpressing and Letrozole resistant cell lines and also studies its mechanism of action in inhibition of breast cancer cell proliferation.

Crosstalk between the peroxisome proliferator-activated receptor γ (PPARγ) and the vitamin D receptor (VDR) in human breast cancer cells: PPARγ binds to VDR and inhibits 1α,25-dihydroxyvitamin D3 mediated transactivation.

Heterodimerization and cross-talk between nuclear hormone receptors often occurs. For example, estrogen receptor alpha (ERα) physically binds to peroxisome proliferator-activated receptor gamma (PPARγ) and inhibits its transcriptional activity. The interaction between PPARγ and the vitamin D receptor (VDR) however, is unknown.

Functional significance of vitamin D receptor FokI polymorphism in human breast cancer cells.

Background: The FokI vitamin D receptor (VDR) polymorphism results in different translation initiation sites on VDR. In the VDRff variant, initiation of translation occurs at the first ATG site, giving rise to a full length VDR protein of 427 amino acids. Conversely, in the VDRFF variant, translation begins at the second ATG site, resulting in a truncated protein with three less amino acids.

Protection against cellular stress by 25-hydroxyvitamin D3 in breast epithelial cells.

25-Hydroxyvitamin D(3) (25(OH)D(3)) is a prohormone and a major vitamin D metabolite. The discovery of (25(OH)D(3)) 1 alpha-hydroxylase in many vitamin D target organs has yielded an increased interest in defining the role(s) of 25(OH)D(3) in these tissues. The etiology of cancer appears to be complex and multi-factorial.

Functionality of unliganded VDR in breast cancer cells: repressive action on CYP24 basal transcription.

It is well-established that CYP24, an immediate target gene of VDR is upregulated by VDR ligands. This study is focused on the functional role of unliganded VDR by investigating the correlation between the expression of VDR protein and basal mRNA levels of CYP24 in breast cancer cell lines. Analyses of multiple breast cancer cell lines demonstrated an inverse correlation between VDR protein expression and CYP24 mRNA expression levels; while in the presence of ligand, VDR protein level was positively correlated with CYP24 expression.

Interferon-inducible IFI16, a negative regulator of cell growth, down-regulates expression of human telomerase reverse transcriptase (hTERT) gene.

Background: Increased levels of interferon (IFN)-inducible IFI16 protein (encoded by the IFI16 gene located at 1q22) in human normal prostate epithelial cells and diploid fibroblasts (HDFs) are associated with the onset of cellular senescence. However, the molecular mechanisms by which the IFI16 protein contributes to cellular senescence-associated cell growth arrest remain to be elucidated. Here, we report that increased levels of IFI16 protein in normal HDFs and in HeLa cells negatively regulate the expression of human telomerase reverse transcriptase (hTERT) gene.

Expression of an IFN-inducible cellular senescence gene, IFI16, is up-regulated by p53.

IFN-inducible IFI16 protein (encoded by IFI16 gene at 1q23.1) is the human member of the IFN-inducible structurally related p200 family proteins. Increased expression of the IFI16 protein, a positive modulator of p53-mediated transcription, in normal old human diploid fibroblasts (HDF) is associated with cellular senescence-mediated cell growth arrest.

Expression of androgen receptor is negatively regulated by p53.

Increased expression of androgen receptor (AR) in prostate cancer (PC) is associated with transition to androgen independence. Because the progression of PC to advanced stages is often associated with the loss of p53 function, we tested whether the p53 could regulate the expression of AR gene. Here we report that p53 negatively regulates the expression of AR in prostate epithelial cells (PrECs).