Many roads lead to oncogene-induced senescence

Courtois-Cox, Stéphanie; Jones, Spencer S.; Cichowski, Karen

doi:10.1038/sj.onc.1210950

Cited by 327 publications

(317 citation statements)

References 57 publications

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“…5B show an up to 4-fold increase in luciferase activity after OTX2 induction in MED8A-OTX2 cells, but not in MED8A-control cells or in MED8A-OTX2 cells transfected with a mutated reporter construct. These data suggest that P53 activity may play a role in the OTX2-induced senescence in MED8A, comparable to the known role of P53 in senescence induced by other oncogenes (21,22).…”

Section: Otx2 Expression Results In P53 Pathway Activation In Med8a Csupporting

confidence: 56%

“…The P53 pathway is responsive to cell cycle stress and is involved in senescence (21,22). We therefore asked whether this pathway was activated after OTX2 induction in MED8A cells.…”

Section: Otx2 Expression Results In P53 Pathway Activation In Med8a Cmentioning

confidence: 99%

“…Although, in most studies, these experiments were conducted in primary fibroblasts or other primary cell lines, oncogene-induced senescence has also been described in tumor cell lines (37,38). The molecular mechanisms underlying oncogene-induced senescence are complex, but most signals seem to converge on the RB and P53 pathways (22), as observed in MED8A cells. Accordingly, virtually all human cancers lack functional RB and P53 pathways and thereby escape from senescence (39).…”

Section: Discussionmentioning

confidence: 99%

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Regulation of Cell Cycle Genes and Induction of Senescence by Overexpression of OTX2 in Medulloblastoma Cell Lines

Bunt

Haas

Hasselt

et al. 2010

Molecular Cancer Research

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The transcription factor orthodenticle homeobox 2 (OTX2) has been implicated in the pathogenesis of medulloblastoma, as it is often highly expressed and sometimes amplified in these tumors. Little is known of the downstream pathways regulated by OTX2. We therefore generated MED8A and DAOY medulloblastoma cell lines with doxycycline-inducible OTX2 expression. In both cell lines, OTX2 inhibited proliferation and induced a senescencelike phenotype with senescence-associated β-galactosidase activity. Expression profiles of time series after OTX2 induction in MED8A showed early upregulation of cell cycle genes related to the G 2 -M phase, such as AURKA, CDC25C, and CCNG2. Paradoxically, G 1 -S phase genes such as MYC, CDK4, CDK6, CCND1, and CCND2 were strongly downregulated, in line with the observed G 1 arrest. ChIP-on-chip analyses of OTX2 binding to promoter regions in MED8A and DAOY showed a strong enrichment for binding to the G 2 -M genes, suggesting a direct activation. Their mRNA expression correlated with OTX2 expression in primary tumors, underscoring the in vivo relevance of this regulation. OTX2 induction activated the P53 pathway in MED8A, but not in DAOY, which carries a mutated P53 gene. In DAOY cells, senescence-associated secretory factors, such as interleukin-6 and insulin-like growth factor binding protein 7, were strongly upregulated after OTX2 induction. We hypothesize that the imbalance in cell cycle stimulation by OTX2 leads to cellular senescence either by activating the P53 pathway or through the induction of secretory factors. Our data indicate that OTX2 directly induces a series of cell cycle genes but requires cooperating genes for an oncogenic acceleration of the cell cycle.

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Section: Otx2 Expression Results In P53 Pathway Activation In Med8a Csupporting

confidence: 56%

“…The P53 pathway is responsive to cell cycle stress and is involved in senescence (21,22). We therefore asked whether this pathway was activated after OTX2 induction in MED8A cells.…”

Section: Otx2 Expression Results In P53 Pathway Activation In Med8a Cmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Regulation of Cell Cycle Genes and Induction of Senescence by Overexpression of OTX2 in Medulloblastoma Cell Lines

Bunt

Haas

Hasselt

et al. 2010

Molecular Cancer Research

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show abstract

“…Recently, substantial evidence has identified cellular senescence as an alternative tumour suppressor mechanism to apoptosis (Courtois-Cox et al, 2008). Supporting this function, following oncogene activation, senescent cells can be found in pre-malignant lesions but not in malignant tumours (Collado et al, 2005), identifying an involvement of cellular senescence in preventing tumour progression.…”

mentioning

confidence: 97%

Cellular senescence induced by aberrant MAD2 levels impacts on paclitaxel responsiveness in vitro

et al. 2009

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BACKGROUND: The mitotic arrest deficiency protein 2 (MAD2) is a key component of the mitotic spindle assembly checkpoint, monitoring accurate chromosomal alignment at the metaphase plate before mitosis. MAD2 also has a function in cellular senescence and in a cell's response to microtubule inhibitory (MI) chemotherapy exemplified by paclitaxel. METHODS: Using an siRNA approach, the impact of MAD2 down-regulation on cellular senescence and paclitaxel responsiveness was investigated. The endpoints of senescence, cell viability, migration, cytokine expression, cell cycle analysis and anaphase bridge scoring were carried out using standard approaches. RESULTS: We show that MAD2 down-regulation induces premature senescence in the MCF7 breast epithelial cancer cell line. These MAD2-depleted (MAD2k) cells are also significantly replicative incompetent but retain viability. Moreover, they show significantly higher levels of anaphase bridges and polyploidy compared to controls. In addition, these cells secrete higher levels of IL-6 and IL-8 representing key components of the senescence-associated secretory phenotype (SASP) with the ability to impact on neighbouring cells. In support of this, MAD2k cells show enhanced migratory ability. At 72 h after paclitaxel, MAD2k cells show a significant further induction of senescence compared with paclitaxel naive controls. In addition, there are significantly more viable cells in the MAD2k MCF7 cell line after paclitaxel reflecting the observed increase in senescence. CONCLUSION: Considering that paclitaxel targets actively dividing cells, these senescent cells will evade cytotoxic kill. In conclusion, compromised MAD2 levels induce a population of senescent cells resistant to paclitaxel.

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“…The presence of senescent cells in benign lesions, but not advanced malignant tumors, suggests that senescence barriers must be dismantled during oncogenic progression. 38 In the case of OSM-induced senescence, persistent STAT3 activation represses MYC (c-MYC) expression and engages a p16-and p53-independent cell cycle arrest that is accompanied by many senescence-associated characteristics, including an enlarged flattened morphology and b-galactosidase (b-Gal) activity. 19,39,40 While OSM-induced MYC repression is associated with senescence, ectopic expression of MYC from a constitutive promoter prevents senescence and alters the response to OSM from tumor-suppressive to tumor-promoting.…”

Section: Introductionmentioning

confidence: 99%

STAT3-mediated SMAD3 activation underlies Oncostatin M-induced Senescence

et al. 2017

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Cytokines in the developing tumor microenvironment (TME) can drive transformation and subsequent progression toward metastasis. Elevated levels of the Interleukin-6 (IL-6) family cytokine Oncostatin M (OSM) in the breast TME correlate with aggressive, metastatic cancers, increased tumor recurrence, and poor patient prognosis. Paradoxically, OSM engages a tumor-suppressive, Signal Transducer and Activator of Transcription 3 (STAT3)-dependent senescence response in normal and non-transformed human mammary epithelial cells (HMEC). Here, we identify a novel link between OSM-activated STAT3 signaling and the Transforming Growth Factor-b (TGF-b) signaling pathway that engages senescence in HMEC. Inhibition of functional TGF-b/SMAD signaling by expressing a dominant-negative TGF-b receptor, treating with a TGF-b receptor inhibitor, or suppressing SMAD3 expression using a SMAD3-shRNA prevented OSMinduced senescence. OSM promoted a protein complex involving activated-STAT3 and SMAD3, induced the nuclear localization of SMAD3, and enhanced SMAD3-mediated transcription responsible for senescence. In contrast, expression of MYC (c-MYC) from a constitutive promoter abrogated senescence and strikingly, cooperated with OSM to promote a transformed phenotype, epithelial-mesenchymal transition (EMT), and invasiveness. Our findings suggest that a novel STAT3/SMAD3-signaling axis is required for OSM-mediated senescence that is coopted during the transformation process to confer aggressive cancer cell properties. Understanding how developing cancer cells bypass OSM/STAT3/SMAD3-mediated senescence may help identify novel targets for future "pro-senescence" therapies aiming to reengage this hidden tumor-suppressive response.

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Many roads lead to oncogene-induced senescence

Cited by 327 publications

References 57 publications

Regulation of Cell Cycle Genes and Induction of Senescence by Overexpression of OTX2 in Medulloblastoma Cell Lines

Regulation of Cell Cycle Genes and Induction of Senescence by Overexpression of OTX2 in Medulloblastoma Cell Lines

Cellular senescence induced by aberrant MAD2 levels impacts on paclitaxel responsiveness in vitro

STAT3-mediated SMAD3 activation underlies Oncostatin M-induced Senescence

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