Oncogene-Induced Senescence Relayed by an Interleukin-Dependent Inflammatory Network

senescence is triggered by various cellular stresses that result in genomic lesions and DnA damage response activation. However, the role of chromatin and DnA replication in senescence induction remains elusive. Here we show that downregulation of p300 histone acetyltransferase activity induces senescence by a mechanism that is independent of the activation of p53, p21 CIP1 and p16 InK4A . This inhibition leads to a global H3, H4 hypoacetylation, initiating senescence-associated heterochromatic foci formation during s phase, together with a global decrease in replication fork velocity, and alteration of DnA replication timing. This replicative stress occurs without DnA damage and checkpoint activation, but results in a robust G2/m cell cycle arrest, within only one cell cycle. These results provide new insights into the control of s-phase progression by p300, and identify an unexpected chromatindependent alternative mechanism for senescence induction, which could possibly be exploited to treat cancer by senescence induction without generating further DnA damage.

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“…For coomassie staining, 2×10 5 cells were seeded into 6-well plates, and fixed and stained 8-12 days after the beginning of the treatment 48 .…”

Section: Methodsmentioning

confidence: 99%

p53 and p16INK4A independent induction of senescence by chromatin-dependent alteration of S-phase progression

et al. 2011

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“…Chemokines -and CXCL8 in particularhave been associated with the phenomenon of cellular senescence [87,88]. CXCR2 and its ligands are secreted during senescence in a NFkB and p53-dependent way and reinforce senescence [87,89]. It is envisaged that in malignancy CXCR2 disregulation or p53 mutation disable this chemokine dependent control pathway, unleashing the pro-tumorigenic inflammatory paracrine functions of chemokines.…”

Section: Tumor Cell Survival and Proliferationmentioning

confidence: 99%

Chemokines in cancer related inflammation

Allavena

Germano

Marchesi

et al. 2011

Experimental Cell Research

197

137

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Chemokines are key players of the cancer-related inflammation. Chemokine ligands and receptors are downstream of genetic events that cause neoplastic transformation and are abundantly expressed in chronic inflammatory conditions which predispose to cancer. Components of the chemokine system affect multiple pathways of tumor progression including: leukocyte recruitment, neo-angiogenesis, tumor cell proliferation and survival, invasion and metastasis.Evidence in pre-clinical and clinical settings suggests that the chemokine system represents a valuable target for the development of innovative therapeutic strategies

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“…Two independent groups reported that cells undergoing OIS secrete CXCR2-binding chemokines and IL-6 through the activation of 2 pro-inflammatory transcription factors, C/EBP-β and NF-κB [13,14]. In human colon adenomas, Mukaida 5 CXCL8/IL-8 specifically colocalizes with arrested p16 INK4A -positive epithelium [13].…”

Section: Direct Effects On Cancer Cellsmentioning

confidence: 99%