A Senescence Program Controlled by p53 and p16INK4a Contributes to the Outcome of Cancer Therapy

Schmitt, Clemens A.; Fridman, Jordan S.; Yang, Meng; Lee, Soyoung; Baranov, Eugene; Hoffman, Robert M.; Lowe, Scott W.

doi:10.1016/s0092-8674(02)00734-1

Cited by 965 publications

(882 citation statements)

References 36 publications

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“…Growing evidence indicate that some tumor cells treated with chemotherapeutic drugs could escape apoptosis by developing cell-cycle arrest leading to senescence [40,41]. We hypothesize that TRAIL is capable to induce senescence that could help tumor cells to escape apoptosis.…”

Section: Trail Induced Senescence-like Phenotype (Slp) Of Tumor Cellsmentioning

confidence: 87%

Multiple effects of TRAIL in human carcinoma cells: Induction of apoptosis, senescence, proliferation, and cytokine production

Levina

Marrangoni

DeMarco

et al. 2008

Experimental Cell Research

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TRAIL is a death ligand that induces apoptosis in malignant but not normal cells. Recently the ability of TRAIL to induce proliferation in apoptosis-resistant normal and malignant cells was reported. In this study, we analyzed TRAIL effects in apoptosis sensitive MCF7, OVCAR3 and H460 human tumor cell lines. TRAIL at low concentrations preferentially induced cell proliferation. At 100 ng/ ml apoptotic death was readily observed, however surviving cells acquired higher proliferative capacity. TRAIL stimulated production of several cytokines, IL-8, RANTES, MCP-1 and bFGF, and activation of caspases 1 and 8 was essential for this effect. Antibodies to IL-8, RANTES, and bFGF blocked TRAIL-induced cell proliferation and further stimulated apoptosis. For the first time, we report that high TRAIL concentrations induced cell senescence as determined by altered morphology and expression of several senescence markers: SA-β-gal, p21 Waf1/Cip1 , p16 INK4a , and HMGA. Caspase 9 inhibition protected TRAIL-treated cells from senescence, whereas inhibition of caspases 1 and 8 increased yield of SLP cells. In conclusion, in cultured human carcinoma cells, TRAIL therapy results in three functional outcomes, apoptosis, proliferation and senescence. TRAIL induced proapoptotic and prosurvival responses correlate with strength of signaling. TRAIL-induced cytokine production is responsible for its proliferative and prosurvival effects.

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Section: Trail Induced Senescence-like Phenotype (Slp) Of Tumor Cellsmentioning

confidence: 87%

Multiple effects of TRAIL in human carcinoma cells: Induction of apoptosis, senescence, proliferation, and cytokine production

Levina

Marrangoni

DeMarco

et al. 2008

Experimental Cell Research

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“…Targeting DDR pathways to improve cancer treatment F Al-Ejeh et al a wild-type p53 or p16 model of Burkitt's lymphoma revealed that responses to cyclophosphamide correlated with increases in the senescence-associated marker bgalactosidase (SA-b-gal) that is lost when p53 or p16 mutations were introduced (Schmitt et al, 2002). Tissuespecific increases of SA-b-gal were associated with low p53 staining and high p16 staining in patients receiving induction chemotherapy for breast cancer (te Poele et al, 2002).…”

Section: Clinical Relevance Of Cell Death Pathwaysmentioning

confidence: 99%

Harnessing the complexity of DNA-damage response pathways to improve cancer treatment outcomes

et al. 2010

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“…Recent studies demonstrated that the ARF tumor suppressor inhibits cell cycle through p53-dependent and p53-independent mechanisms. [38][39][40][41][42][43] Moreover, ARF/p53 double-null B cells are more resistant to Myc-induced apoptosis than cells lacking ARF or p53 alone. 31 At face value, these results imply that the p53-independent ARF function might be selected against in MIF-KO Em-Myc B-lymphomas.…”

Section: Mif-deficient Lymphomas Contain P53 Inactivating Mutations Amentioning

confidence: 99%

MIF loss impairs Myc-induced lymphomagenesis

et al. 2005

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Macrophage migration inhibitory factor (MIF) is a potent regulator of inflammation and cell growth. Using the El-Myc lymphoma mouse model, we demonstrate that loss of MIF markedly delays the onset of B-cell lymphoma development in vivo. The molecular basis for this MIF-loss-induced phenotype is the perturbed DNA-binding activity of E2F factors and the concomitantly enhanced tumor suppressor activity of the p53 pathway. Accordingly, premalignant MIF-null El-Myc Bcells are predisposed to delayed S-phase progression and increased apoptosis. MIF-deficient lymphomas that do arise under these conditions contain frequent ARF deletions and p53 inactivating mutations. Conversely, MIF expression is retained in tumors developed by wild-type El-Myc animals, and the presence of one or both MIF alleles is sufficient to accelerate the development of Myc-induced lymphomas. Collectively, these results indicate that MIF promotes Mycmediated tumorigenesis, at least in the B-lymphoid compartment, and implicate MIF as a mediator of malignant cell growth in vivo.

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A Senescence Program Controlled by p53 and p16INK4a Contributes to the Outcome of Cancer Therapy

Cited by 965 publications

References 36 publications

Multiple effects of TRAIL in human carcinoma cells: Induction of apoptosis, senescence, proliferation, and cytokine production

Multiple effects of TRAIL in human carcinoma cells: Induction of apoptosis, senescence, proliferation, and cytokine production

Harnessing the complexity of DNA-damage response pathways to improve cancer treatment outcomes

MIF loss impairs Myc-induced lymphomagenesis

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