Induced p53 expression in lung cancer cell line promotes cell senescence and differentially modifies the cytotoxicity of anti-cancer drugs

Wang, Yingcai; Blandino, Giovanni; Oren, Moshe

doi:10.1038/sj.onc.1202113

Cited by 93 publications

(72 citation statements)

References 27 publications

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“…The induction of senescence by p21 waf takes 4 ± 6 days ( Figure 4) and results in loss of colony formation capability. Previous work on overexpression of p53 in the EJ cell line and our results on overexpression of p53 in H1299 cells (Wang et al, 1998) also demonstrated that the p53-dependent growth arrest resulted in senescence (Sugrue et al, 1997). This raised the possibility that senescence may be an important mechanism which prevents tumorigenesis and may be an alternative to apoptosis.…”

Section: Discussionsupporting

confidence: 71%

Induced p21waf expression in H1299 cell line promotes cell senescence and protects against cytotoxic effect of radiation and doxorubicin

1999

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The CDK inhibitor p21 waf is a principal mediator of p53 function but can also be transactivated by many p53-independent stimuli leading to cell growth arrest or di erentiation. In order to study the function of p21 waf in a p53-de®cient environment, we established an inducible expression of p21 waf in the p53-null lung cancer cell line H1299, based on the muristerone-regulated system. Overexpression of p21 waf led cells to growth arrest which after several days became irreversible and the arrested cells acquired a senescent phenotype as judged by cell shape, the senescence-associated b-gal marker and inhibition of colony formation. The e ect of p21 waf overexpression, in the absence of p53, on the cytotoxicity caused by irradiation, doxorubicin and taxol was studied. Expression of p21 waf provided protection against the cytotoxic e ect of radiation and doxorubicin but not of taxol. These results are relevant to treatment of cancer when p53 is inactive.

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Section: Discussionsupporting

confidence: 71%

Induced p21waf expression in H1299 cell line promotes cell senescence and protects against cytotoxic effect of radiation and doxorubicin

1999

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“…The induction of a senescent-like phenotype has also been demonstrated in tumour-derived cell lines. In particular, activation of a senescence programme in neoplastic cells has been obtained either by reintroduction of critical regulators of replicative senescence [25,37] or by treatment with anti-cancer agents [42]. Most interestingly, expression of several CKI, in both normal and tumour cells [23,24], triggers premature senescence.…”

Section: Induction Of a Senescent-like Phenotypementioning

confidence: 99%

“…Cell lines derived from tumours are generally capable of extended proliferation: indeed, limitless replicative potential represents one of the de novo acquired capabilities of tumour cells, and the ability to repress senescence pathways appears to contribute to tumorigenesis [22]. Accordingly, restoration of senescence regulatory pathways in tumour cells rapidly elicits senescence [23][24][25]. These observations suggest that, in several immortal tumour-derived cell lines, the genetic programme of senescence is repressed, but not lost, in such a way that it can be reactivated by expression of critical regulators.…”

Section: Introductionmentioning

confidence: 99%

Bcl-2 activates a programme of premature senescence in human carcinoma cells

Crescenzi

Palumbo

Brady

2003

Biochemical Journal

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The apoptosis regulator Bcl-2 has been shown to modulate cellcycle progression, favouring a quiescent state over a proliferative state, in both normal and tumour cells. We show here that constitutive expression of Bcl-2 in human carcinoma cells results in a cell-cycle arrest that within a few days can become irreversible. Arrested cells acquire a senescent-like phenotype, which consists of several characteristic morphological alterations and increased activity of senescence-associated β-galactosidase. The induction of the premature senescence programme is mediated by inhibition of Cdk2 kinase activity, and p27 KIP1 is required to maintain the senescent phenotype. We propose that the ability to activate an endogenous premature senescence programme allows Bcl-2 to suppress tumour growth. These results suggest that the downregulation of Bcl-2 expression, which has been observed during the development and progression of human carcinoma, is related to the ability of Bcl-2 to severely hamper the growth of carcinoma cells and to induce a permanent cell-cycle arrest, with the features of senescence.

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“…Although cancer cells bypass both replicative and oncogene-induced senescence, the genetic program of senescence in these cells seems to be repressed, but not lost, in such a way that it can be reactivated by expression of critical regulators. Accordingly, restoration of senescence regulatory pathways in tumor cells rapidly elicits senescence (Wang et al, 1998(Wang et al, , 1999. In addition, a process termed stress-induced or premature senescence can be readily elicited in tumor cells by treatment with sublethal concentrations of conventional anticancer drugs (Chang et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

NF-κB-dependent cytokine secretion controls Fas expression on chemotherapy-induced premature senescent tumor cells

et al. 2011

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Induction of a senescent phenotype in tumor cells has been linked to anticancer immune response, however, the molecular mechanisms mediating these phenomenon have not yet been determined. In this study, we present evidence that induction of premature senescence in human cancer cell lines induces Fas expression, and loss of resistance to Fas-induced apoptosis. Triggering of Fas by using the agonistic antibody CH11 or the recombinant ligand APO010, activates an apoptotic pathway responsible for cell death. Secretion of pro-inflammatory cytokines by the senescent cells, particularly TNF-a and IFN-c, mediates Fas upregulation. Indeed, treatment of proliferating cancer cell lines with TNF-a and IFN-c, upregulates Fas expression, while blocking TNF-a and IFN-c by using neutralizing antibodies, decreases Fas expression in senescent cells. We also demonstrate that NF-jB has a central role in controlling the senescence-associated secretory phenotype (SASP) by the premature senescent cells, and that TNF-a and IFN-c, transcriptionally controlled by NF-jB, are the main mediators of Fas upregulation. Our data suggest the existence of an NF-jB-dependent autocrine loop, mediated by TNF-a and IFN-c, responsible for expression of Fas on the surface of senescent cells, and for their killing.

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Induced p53 expression in lung cancer cell line promotes cell senescence and differentially modifies the cytotoxicity of anti-cancer drugs

Cited by 93 publications

References 27 publications

Induced p21waf expression in H1299 cell line promotes cell senescence and protects against cytotoxic effect of radiation and doxorubicin

Induced p21waf expression in H1299 cell line promotes cell senescence and protects against cytotoxic effect of radiation and doxorubicin

Bcl-2 activates a programme of premature senescence in human carcinoma cells

NF-κB-dependent cytokine secretion controls Fas expression on chemotherapy-induced premature senescent tumor cells

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