scholarly journals Crosstalk between Plk1, p53, cell cycle, and G2/M DNA damage checkpoint regulation in cancer: computational modeling and analysis

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Yongwoon Jung ◽  
Pavel Kraikivski ◽  
Sajad Shafiekhani ◽  
Scott S. Terhune ◽  
Ranjan K. Dash
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cell Cycle Progression ◽  
Dna Damage Checkpoint ◽  
Cycle Progression ◽  
Cycle Arrest ◽  
Gene Perturbations

AbstractDifferent cancer cell lines can have varying responses to the same perturbations or stressful conditions. Cancer cells that have DNA damage checkpoint-related mutations are often more sensitive to gene perturbations including altered Plk1 and p53 activities than cancer cells without these mutations. The perturbations often induce a cell cycle arrest in the former cancer, whereas they only delay the cell cycle progression in the latter cancer. To study crosstalk between Plk1, p53, and G2/M DNA damage checkpoint leading to differential cell cycle regulations, we developed a computational model by extending our recently developed model of mitotic cell cycle and including these key interactions. We have used the model to analyze the cancer cell cycle progression under various gene perturbations including Plk1-depletion conditions. We also analyzed mutations and perturbations in approximately 1800 different cell lines available in the Cancer Dependency Map and grouped lines by genes that are represented in our model. Our model successfully explained phenotypes of various cancer cell lines under different gene perturbations. Several sensitivity analysis approaches were used to identify the range of key parameter values that lead to the cell cycle arrest in cancer cells. Our resulting model can be used to predict the effect of potential treatments targeting key mitotic and DNA damage checkpoint regulators on cell cycle progression of different types of cancer cells.

scholarly journals Computational Model of G2-M DNA Damage Checkpoint Regulation in Normal and p53-null Cancer Cells

2020 ◽  
Author(s):  
Yongwoon Jung ◽  
Pavel Kraikivski
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Computational Model ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Cell Cycle Progression ◽  
Dna Damage Checkpoint ◽  
Cycle Progression ◽  
Normal Cells ◽  
Cycle Arrest

AbstractCancer and normal cells can respond differently to the same stressful conditions. Their dynamic responses under normal and stressful conditions are governed by complex molecular regulatory networks. We developed a computational model of G2-M DNA damage checkpoint regulation to study normal and cancer cell cycle progression under normal and stressful conditions. Our model is successful in explaining cancer cell cycle arrest in conditions when some cell cycle and DNA damage checkpoint regulators are inhibited, whereas the same conditions only delay entry into mitosis in normal cells. We use the model to explain known phenotypes of gene deletion mutants and predict phenotypes of yet uncharacterized mutants in normal and cancer cells. We also use sensitive analyses to identify the ranges of model parameter values that lead to the cell cycle arrest in cancer cells. Our results can be used to predict the effect of a potential treatment on cell cycle progression of normal and cancer cells.

scholarly journals Anticancer Activity of Cynomorium coccineum

Cancers ◽  
2018 ◽  
Vol 10 (10) ◽  
pp. 354 ◽  
Author(s):  
Mouna Sdiri ◽  
Xiangmin Li ◽  
William Du ◽  
Safia El-Bok ◽  
Yi-Zhen Xie ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Anticancer Activity ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cell Cycle Progression ◽  
Cycle Progression

The extensive applications of Cynomorium species and their rich bioactive secondary metabolites have inspired many pharmacological investigations. Previous research has been conducted to examine the biological activities and numerous interesting pharmaceutical activities have been reported. However, the antitumor activities of these species are unclear. To understand the potential anticancer activity, we screened Cynomorium coccineum and Cynomorium songaricum using three different extracts of each species. In this study, the selected extracts were evaluated for their ability to decrease survival rates of five different cancer cell lines. We compared the cytotoxicity of the three different extracts to the anticancer drug vinblastine and one of the most well-known medicinal mushrooms Amaurederma rude. We found that the water and alcohol extracts of C. coccineum at the very low concentrations possessed very high capacity in decreasing the cancer cells viability with a potential inhibition of tumorigenesis. Based on these primitive data, we subsequently tested the ethanol and the water extracts of C. coccineum, respectively in in vitro and in vivo assays. Cell cycle progression and induction of programmed cell death were investigated at both biological and molecular levels to understand the mechanism of the antitumor inhibitory action of the C. coccineum. The in vitro experiments showed that the treated cancer cells formed fewer and smaller colonies than the untreated cells. Cell cycle progression was inhibited, and the ethanol extract of C. coccineum at a low concentration induced accumulation of cells in the G1 phase. We also found that the C. coccineum’s extracts suppressed viability of two murine cancer cell lines. In the in vivo experiments, we injected mice with murine cancer cell line B16, followed by peritoneal injection of the water extract. The treatment prolonged mouse survival significantly. The tumors grew at a slower rate than the control. Down-regulation of c-myc expression appeared to be associated with these effects. Further investigation showed that treatment with C. coccineum induced the overexpression of the tumor suppressor Foxo3 and other molecules involved in inducing autophagy. These results showed that the C. coccineum extract exerts its antiproliferative activity through the induction of cell death pathway. Thus, the Cynomorium plants appear to be a promising source of new antineoplastic compounds.

scholarly journals The G(2) DNA damage checkpoint targets both Wee1 and Cdc25

2000 ◽  
Vol 113 (10) ◽  
pp. 1727-1736 ◽  
Author(s):  
J.M. Raleigh ◽  
M.J. O'Connell
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Progression ◽  
Dna Damage Checkpoint ◽  
Checkpoint Control ◽  
Down Regulation ◽  
Cycle Progression ◽  
Cycle Arrest ◽  
Checkpoint Pathway

The onset of mitosis is controlled by the cyclin dependent kinase Cdc2p. Cdc2p activity is controlled through the balance of phosphorylation and dephosphorylation of tyrosine-15 (Y15) by the Wee1p kinase and Cdc25p phosphatase. In the fission yeast Schizosaccharomyces pombe, detection of DNA damage in G(2) activates a checkpoint that prevents entry into mitosis through the maintenance of Y15 phosphorylation of Cdc2p, thus ensuring DNA repair precedes chromosome segregation. The protein kinase Chk1p is the endpoint of this checkpoint pathway. We have previously reported that overexpression of Chk1p causes a wee1(+)-dependent G(2) arrest, and this or irradiation leads to hyperphosphorylation of Wee1p. Moreover, Chk1p directly phosphorylates Wee1p in vitro. These data suggested that Wee1p is a key target of Chk1p action in checkpoint control. However, cells lacking wee1(+) are checkpoint proficient and sustained Chk1p overexpression arrests cell cycle progression independently of Wee1p. Therefore, up-regulation of Wee1p alone cannot enforce a checkpoint arrest. Chk1p can also phosphorylate Cdc25p in vitro. These phosphorylation events are thought to promote the interaction with 14–3-3 proteins the cytoplasmic retention of the 14–3-3/Cdc25p complexes. However, we show here that the G(2) DNA damage checkpoint is intact in cells that regulate mitotic entry independently of Cdc25p. Further, these cells are still sensitive to Chk1p-mediated arrest, and so down-regulation of Cdc25p is also insufficient to regulate checkpoint arrest. Conversely, inactivation of both wee1(+) and cdc25(+)abolishes checkpoint control. We also show that activation of the G(2) DNA damage checkpoint induces a transient increase in Wee1p levels. We conclude that the G(2) DNA damage checkpoint simultaneously signals via both up-regulation of Wee1p and down-regulation of Cdc25p, thus providing a double-lock mechanism to ensure cell cycle arrest and genomic stability.

scholarly journals Synthesis of 2,6-Diamino-Substituted Purine Derivatives and Evaluation of Cell Cycle Arrest in Breast and Colorectal Cancer Cells

Molecules ◽  
2018 ◽  
Vol 23 (8) ◽  
pp. 1996 ◽  
Author(s):  
Bartolomeo Bosco ◽  
Andrea Defant ◽  
Andrea Messina ◽  
Tania Incitti ◽  
Denise Sighel ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Density Functional ◽  
Cell Cycle Progression ◽  
Cycle Arrest ◽  
M Phase

Reversine is a potent antitumor 2,6-diamino-substituted purine acting as an Aurora kinases inhibitor and interfering with cancer cell cycle progression. In this study we describe three reversine-related molecules, designed by docking calculation, that present structural modifications in the diamino units at positions 2 and 6. We investigated the conformations of the most stable prototropic tautomers of one of these molecules, the N6-cyclohexyl-N6-methyl-N2-phenyl-7H-purine-2,6-diamine (3), by Density Functional Theory (DFT) calculation in the gas phase, water and chloroform, the last solvent considered to give insights into the detection of broad signals in NMR analysis. In all cases the HN(9) tautomer resulted more stable than the HN(7) form, but the most stable conformations changed in different solvents. Molecules 1–3 were evaluated on MCF-7 breast and HCT116 colorectal cancer cell lines showing that, while being less cytotoxic than reversine, they still caused cell cycle arrest in G2/M phase and polyploidy. Unlike reversine, which produced a pronounced cell cycle arrest in G2/M phase in all the cell lines used, similar concentrations of 1–3 were effective only in cells where p53 was deleted or down-regulated. Therefore, our findings support a potential selective role of these structurally simplified, reversine-related molecules in p53-defective cancer cells.

The Capacity of the Hypomethylating Agents Azacytidine and Decitabine to Induce Apoptosis and Cell Cycle Arrest Depends on the Activation of the DNA-Damage Response Pathway.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1655-1655
Author(s):  
Simone Boehrer ◽  
Lionel Ades ◽  
Nicolas Tajeddine ◽  
Lorenzo Galluzzi ◽  
Stephane de Botton ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Dna Damage Response ◽  
Cell Cycle Progression ◽  
Hypomethylating Agents ◽  
Cycle Progression ◽  
Cycle Arrest ◽  
Damage Response

Abstract Background: The hypomethylating agents azacytidine (AZA) and decitabine (DEC) have shown clinical efficacy in patients (pts) with MDS. There is in vitro evidence that both agents, in addition to their hypomethylating effect, also function by inducing apoptosis, cell cycle arrest and/or the activation of a DNA damage response (DDR). However, the exact contributions of those mechanisms of action and their functional interdependence remain to be defined. Methods: A panel of MDS (P39, MDS-1)- and AML (HL-60, KG-1)-derived cell lines were incubated with increasing dosages of AZA (1–2μM) and DEC (1–2μM) and the drugs capacity to induce apoptosis (DiOC6(3)/PI), cell cycle arrest (PI) and/or a DDR (immunoflourescence staining of P-ATM, P-Chk-1, P-Chk-2, γ-H2AX) were assessed in absence and presence of the ATM-inhibitor KU-55933 and the Chk-1 inhibitor UCN-01. Results: We show that both drugs induced dose-dependent apoptosis in myeloid cell lines: whereas AZA increased apoptosis in KG-1 and HL-60 by about 10% (48h, 2μM) the respective incubation with DEC augmented apoptosis by about 20% (HL-60) to 30% (KG-1). P39 cells were resistant to AZA and increased apoptosis by 15% after 48h of 2μM DEC, and MDS-1 cells were resistant to both drugs. In addition, both drugs induced a G2/M-arrest in P39 (+15% after 48h with 2μM of AZA or DEC) and HL-60 (+20% after 48h with 2μM of AZA or DEC) cells, but not in KG-1 and MDS-1 cells. Noteworthy, both drugs induced a DDR in the apoptosis-sensitive KG-1 cells (but not P39 cells) as evidenced by the appearance of nuclear P-ATM and γ-H2AX foci. Surprisingly, this activation of P-ATM did not induce the nuclear translocation of P-Chk-1-Ser317 or P-Chk-2-Ser68. To more clearly define the importance of the DDR in AZA- and DEC-induced apoptosis and G2/M-arrest, experiments were recapitulated in the presence of the ATM-inhibitor KU-55933 and the Chk-1 inhibitor UCN-01. Inhibition of ATM abrogated the apoptosis-inducing activity of AZA and DEC in KG-1 cells (without influencing cell cycle progression), whereas inhibition of Chk-1 remained without effect. In contrast, in P39 and HL-60 cells, inhibition of ATM neither affected cell cycle progression, nor sensitivity towards the drugs. Nevertheless, inhibition of Chk-1 by UCN-01 completely abrogated the G2/M-arresting effect of AZA (and diminished that of DEC) in P39 and HL-60 cells. Conclusions: We provide novel evidence for the cell-type dependent capacity of the hypomethylating agents 5-azacytidine and decitabine to induce apoptosis, cell-cycle arrest and DDR in cell lines representing different subtypes of MDS and AML. Moreover, we show the crucial role of ATM and Chk-1 activation – as part of the DDR – in mediating AZA and DEC apoptosis-inducing and cell cycle-arresting effects, respectively, providing evidence that hypomethylating agents confer their beneficial effects by employing different pathways of the DDR.

scholarly journals Effect of Piceatannol on Cell Cycle Progression in Prostate Cancer Cells (P05-005-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Larissa Kido ◽  
Eun-Ryeong Hahm ◽  
Valeria Cagnon ◽  
Mário Maróstica ◽  
Shivendra Singh
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
Cell Cycle Distribution ◽  
Mutant P53 ◽  
Wild Type ◽  
Cycle Progression ◽  
Cycle Arrest

Abstract Objectives Piceatannol (PIC) is a polyphenolic and resveratrol analog that is found in many vegetables consumed by humans. Like resveratrol, PIC has beneficial effects on health due to its anti-inflammatory, anti-oxidative and anti-proliferative features. However, the molecular targets of PIC in prostate cancer (PCa), which is the second most common cancer in men worldwide, are still poorly understood. Preventing cancer through dietary sources is a promising strategy to control diseases. Therefore, the aim of present study was to investigate the molecular mechanistic of actions of PIC in PCa cell lines with different genetic background common to human prostate cancer. Methods Human PCa cell lines (PC-3, 22Rv1, LNCaP, and VCaP) were treated with different doses of PIC (5–40 µM) and used for cell viability assay, measurement of total free fatty acids (FFA) and lactate, and cell cycle distribution. Results PIC treatment dose- and time-dependently reduced viability in PC-3 (androgen-independent, PTEN null, p53 null) and VCaP cells (androgen-responsive, wild-type PTEN, mutant p53). Because metabolic alterations, such as increased glucose and lipid metabolism are implicated in pathogenesis of in PCa, we tested if PIC could affect these pathways. Results from lactate and total free fatty acid assays in VCaP, 22Rv1 (castration-resistant, wild-type PTEN, mutant p53), and LNCaP (androgen-responsive, PTEN null, wild-type p53) revealed no effect of PIC on these metabolisms. However, PIC treatment delayed cell cycle progression in G0/G1 phase concomitant with the induction of apoptosis in both LNCaP and 22Rv1 cells, suggesting that growth inhibitory effect of PIC in PCa is associated with cell cycle arrest and apoptotic cell death at least LNCaP and 22Rv1 cells. Conclusions While PIC treatment does not alter lipid or glucose metabolism, cell cycle arrest and apoptosis induction are likely important in anti-cancer effects of PIC. Funding Sources São Paulo Research Foundation (2018/09793-7).

scholarly journals PHF2 histone demethylase prevents DNA damage and genome instability by controlling cell cycle progression of neural progenitors

2019 ◽  
Vol 116 (39) ◽  
pp. 19464-19473 ◽  
Author(s):  
Stella Pappa ◽  
Natalia Padilla ◽  
Simona Iacobucci ◽  
Marta Vicioso ◽  
Elena Álvarez de la Campa ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Genome Stability ◽  
Cell Cycle Progression ◽  
Genome Instability ◽  
Neural Progenitors ◽  
Cycle Progression ◽  
Cycle Arrest ◽  
Biochemical Assays

Histone H3 lysine 9 methylation (H3K9me) is essential for cellular homeostasis; however, its contribution to development is not well established. Here, we demonstrate that the H3K9me2 demethylase PHF2 is essential for neural progenitor proliferation in vitro and for early neurogenesis in the chicken spinal cord. Using genome-wide analyses and biochemical assays we show that PHF2 controls the expression of critical cell cycle progression genes, particularly those related to DNA replication, by keeping low levels of H3K9me3 at promoters. Accordingly, PHF2 depletion induces R-loop accumulation that leads to extensive DNA damage and cell cycle arrest. These data reveal a role of PHF2 as a guarantor of genome stability that allows proper expansion of neural progenitors during development.

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