Methotrexate-induced senescence in human adenocarcinoma cells is accompanied by induction of p21waf1/cip1 expression and lack of polyploidy

Dabrowska, Magdalena; Mosieniak, Grażyna; Skierski, Janusz; Sikora, Ewa; Rode, Wojciech

doi:10.1016/j.canlet.2009.04.015

Cited by 24 publications

(16 citation statements)

References 33 publications

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“…Studies performed by Jackson and Pereira-Smith revealed that senescent cancer cells can be stopped in the G1 or G2 phase of the cell cycle as it is in the case of doxorubicin-treated MCF-7 cells [83] or in the S-phase, as it was shown by us in the case of human colon cancer cells treated with methotrexate [84].…”

Section: Polyploidization Of Cancer Cells Induced To Senescencementioning

confidence: 84%

Polyploidy: The Link Between Senescence and Cancer

Mosieniak¹,

Sikora²

2010

CPD

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Polyploidy, a state of increased number of chromosomes, occurs often in plants and less frequently in animals. Polyploidization is recognized as a part of a developmental program and can be achieved via different mechanisms bypassing certain stages of the cell cycle. However, polyploidization also accompanies some pathological conditions as well as ageing. It is believed that tetraploid cells precede aneuploid ones in the early phases of tumor development. Division of tetraploid cells is restricted by the active tetraploid (4N G1) checkpoint. Tetraploid cells that are able to overcome this checkpoint give rise to increased genomic instability and tumor progression. Recently a cellular senescence program activated by oncogene expression was shown to act as a natural barrier against cancer development. Senescent cells were detected in many benign, but not malignant, human and animal tumors. Senescence can actually block cell transformation provided the 4N G1 checkpoint is active. Cancer cells that escaped the 4N G1 block are still able to undergo senescence upon anticancer treatment. Induction of cancer cell senescence is often correlated with high ploidy formation. Some polyploid cells can escape senescence and give progeny with numerical changes of chromosomes. Divisions of polyploid cancer cells on the road to senescence can be responsible for the ineffectiveness of anticancer therapy. Altogether, this implies polyploidy as a link between cellular senescence, cancer development and possible cancer renewal after treatment.

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Section: Polyploidization Of Cancer Cells Induced To Senescencementioning

confidence: 84%

Polyploidy: The Link Between Senescence and Cancer

Mosieniak¹,

Sikora²

2010

CPD

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“…Seven out of 12 compounds were found to have significantly enhanced senescence in Pten À / À cells as compared to the untreated control (Supplementary Table 1a). Among these seven compounds, we found two bona fide (quinalizarin/CK2i-Q, CX-4945/CK2i-CX) 16,24,25 and one predicted (CK2i-S) 17 casein kinase 2 (CK2) small-molecule inhibitors, two cytotoxic compounds already available in the clinic (Carboplatin, Methotrexate 18,19 ), a KISS1 20,21 and a DKK1 inhibitor (proprietary data of Sibi Spa; Supplementary Table 1a, Supplementary Table 2b and Supplementary Fig. 1b).…”

Section: Resultsmentioning

confidence: 99%

A chemogenomic screening identifies CK2 as a target for pro-senescence therapy in PTEN-deficient tumours

et al. 2015

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Enhancement of cellular senescence in tumours triggers a stable cell growth arrest and activation of an antitumour immune response that can be exploited for cancer therapy. Currently, there are only a limited number of targeted therapies that act by increasing senescence in cancers, but the majority of them are not selective and also target healthy cells. Here we developed a chemogenomic screening to identify compounds that enhance senescence in PTEN-deficient cells without affecting normal cells. By using this approach, we identified casein kinase 2 (CK2) as a pro-senescent target. Mechanistically, we show that Pten loss increases CK2 levels by activating STAT3. CK2 upregulation in Pten null tumours affects the stability of Pml, an essential regulator of senescence. However, CK2 inhibition stabilizes Pml levels enhancing senescence in Pten null tumours. Taken together, our screening strategy has identified a novel STAT3-CK2-PML network that can be targeted for pro-senescence therapy for cancer.

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“…Methotrexate targets the S phase of the cell cycle by inhibiting dihydrofolate reductase (Dabrowska et al 2009), and HR functions in the S/G2 phases of the cell cycle (Mao et al 2008). This prompted us to evaluate whether regulation of homologous recombination repair activity is altered after exposure to methotrexate.…”

Section: Subnuclear Repair Foci Are Inhibited By Methotrexatementioning

confidence: 99%