scholarly journals Opposite Effects of the Triple Target (DNA-PK/PI3K/mTOR) Inhibitor PI-103 on the Radiation Sensitivity of Glioblastoma Cell Lines MO59K and MO59J Differing in DNA-PK and ATM Status

2020 ◽  
Author(s):  
Cholpon S. Djuzenova ◽  
Thomas Fischer ◽  
Astrid Katzer ◽  
Dmitri Sisario ◽  
Tessa Korsa ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
Radiation Treatment ◽  
Radiation Sensitivity ◽  
Future Research ◽  
Mtor Inhibition ◽  
Mutational Status ◽  
Intrinsic Radiosensitivity

Abstract Background: Radiotherapy is routinely used to combat glioblastoma multiforme (GBM). However, the treatment efficacy is often limited by the radioresistance of GBM cells.Methods: Two isogenic GBM lines MO59K and MO59J, differing in intrinsic radiosensitivity and mutational status of DNA-PK and ATM, were analyzed regarding their response to DNA-PK/PI3K/mTOR inhibition by PI-103 in combination with radiation. To this end we assessed colony-forming ability, induction and repair of DNA damage by γH2AX, expression of marker proteins, including those belonging to NHEJ and HR repair pathways, degree of apoptosis, autophagy, and cell cycle alterations.Results: We found that PI-103 radiosensitized MO59K cells but, surprisingly, it induced radiation resistance in MO59J cells. In MO59K cells, combined PI-103 and radiation treatment induced much higher γH2AX expression measured by Western blot as compared to MO59J. Another cell line-specific difference includes diminished expression of p53 in MO59J cells, which was further reduced by PI-103. Additionally, PI-103-treated MO59K cells exhibited an increased expression of the apoptosis marker cleaved PARP. In contrast, PI-103-treated MO59J cells showed an increased level of LC3BII, indicative of cytoprotective autophagy. Moreover, irradiation induced a strong G2 arrest in MO59J cells (~80% vs. ~50% in MO59K), which was, however, partially abolished by PI-103 thus allowing cell-cycle progression of a fraction of cells. In contrast, treatment with PI-103 increased the G2 fraction in irradiated MO59K cells.Conclusions: The triple-target inhibitor PI-103 exerted radiosensitization on MO59K cells, but, unexpectedly, caused radioresistance in the MO59J line, lacking DNA-PK. The difference is most likely due to low expression of the DNA-PK substrate p53 in MO59J cells, which was further reduced by PI-103. This led to less apoptosis as compared to drug-free MO59J cells and enhanced survival via partially abolished cell-cycle arrest. The findings suggest that the lack of DNA-PK-dependent NHEJ in MO59J line might be compensated by DNA-PK independent DSB repair via a yet unknown mechanism. Future research on an extended cell panel should focus on finding ways to enhance the radiosensitivity of cell lines with deficiencies in DNA-PK and ATM, the key proteins involved in the DNA damage response.

scholarly journals Opposite effects of the triple target (DNA-PK/PI3K/mTOR) inhibitor PI-103 on the radiation sensitivity of glioblastoma cell lines proficient and deficient in DNA-PKcs

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Cholpon S. Djuzenova ◽  
Thomas Fischer ◽  
Astrid Katzer ◽  
Dmitri Sisario ◽  
Tessa Korsa ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Radiation Sensitivity ◽  
Mtor Inhibition ◽  
Cycle Arrest ◽  
Mutational Status ◽  
Damage Repair ◽  
Intrinsic Radiosensitivity ◽  
The Difference ◽  
Drug Free

Abstract Background Radiotherapy is routinely used to combat glioblastoma (GBM). However, the treatment efficacy is often limited by the radioresistance of GBM cells. Methods Two GBM lines MO59K and MO59J, differing in intrinsic radiosensitivity and mutational status of DNA-PK and ATM, were analyzed regarding their response to DNA-PK/PI3K/mTOR inhibition by PI-103 in combination with radiation. To this end we assessed colony-forming ability, induction and repair of DNA damage by γH2AX and 53BP1, expression of marker proteins, including those belonging to NHEJ and HR repair pathways, degree of apoptosis, autophagy, and cell cycle alterations. Results We found that PI-103 radiosensitized MO59K cells but, surprisingly, it induced radiation resistance in MO59J cells. Treatment of MO59K cells with PI-103 lead to protraction of the DNA damage repair as compared to drug-free irradiated cells. In PI-103-treated and irradiated MO59J cells the foci numbers of both proteins was higher than in the drug-free samples, but a large portion of DNA damage was quickly repaired. Another cell line-specific difference includes diminished expression of p53 in MO59J cells, which was further reduced by PI-103. Additionally, PI-103-treated MO59K cells exhibited an increased expression of the apoptosis marker cleaved PARP and increased subG1 fraction. Moreover, irradiation induced a strong G2 arrest in MO59J cells (~ 80% vs. ~ 50% in MO59K), which was, however, partially reduced in the presence of PI-103. In contrast, treatment with PI-103 increased the G2 fraction in irradiated MO59K cells. Conclusions The triple-target inhibitor PI-103 exerted radiosensitization on MO59K cells, but, unexpectedly, caused radioresistance in the MO59J line, lacking DNA-PK. The difference is most likely due to low expression of the DNA-PK substrate p53 in MO59J cells, which was further reduced by PI-103. This led to less apoptosis as compared to drug-free MO59J cells and enhanced survival via partially abolished cell-cycle arrest. The findings suggest that the lack of DNA-PK-dependent NHEJ in MO59J line might be compensated by DNA-PK independent DSB repair via a yet unknown mechanism.

scholarly journals Resistance of Hypoxic Cells to Ionizing Radiation Is Mediated in Part via Hypoxia-Induced Quiescence

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 610
Author(s):  
Apostolos Menegakis ◽  
Rob Klompmaker ◽  
Claire Vennin ◽  
Aina Arbusà ◽  
Maartje Damen ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Lines ◽  
Cancer Cell ◽  
Radiation Treatment ◽  
Large Fraction ◽  
Radiation Sensitivity ◽  
Cancer Cell Lines ◽  
Cycle Phase ◽  
Multicellular Spheroids ◽  
Phase Duration

Double strand breaks (DSBs) are highly toxic to a cell, a property that is exploited in radiation therapy. A critical component for the damage induction is cellular oxygen, making hypoxic tumor areas refractory to the efficacy of radiation treatment. During a fractionated radiation regimen, these hypoxic areas can be re-oxygenated. Nonetheless, hypoxia still constitutes a negative prognostic factor for the patient’s outcome. We hypothesized that this might be attributed to specific hypoxia-induced cellular traits that are maintained upon reoxygenation. Here, we show that reoxygenation of hypoxic non-transformed RPE-1 cells fully restored induction of DSBs but the cells remain radioresistant as a consequence of hypoxia-induced quiescence. With the use of the cell cycle indicators (FUCCI), cell cycle-specific radiation sensitivity, the cell cycle phase duration with live cell imaging, and single cell tracing were assessed. We observed that RPE-1 cells experience a longer G1 phase under hypoxia and retain a large fraction of cells that are non-cycling. Expression of HPV oncoprotein E7 prevents hypoxia-induced quiescence and abolishes the radioprotective effect. In line with this, HPV-negative cancer cell lines retain radioresistance, while HPV-positive cancer cell lines are radiosensitized upon reoxygenation. Quiescence induction in hypoxia and its HPV-driven prevention was observed in 3D multicellular spheroids. Collectively, we identify a new hypoxia-dependent radioprotective phenotype due to hypoxia-induced quiescence that accounts for a global decrease in radiosensitivity that can be retained upon reoxygenation and is absent in cells expressing oncoprotein E7.

Disrupting NEDD8-Mediated Protein Turnover with MLN4924 Significantly Augments the Efficacy of Cytarabine

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3255-3255
Author(s):  
Steffan T Nawrocki ◽  
Kevin R Kelly ◽  
Kelli Oberheu ◽  
Devalingam Mahalingam ◽  
Peter G Smith ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Signal Transduction ◽  
Dna Damage ◽  
Elderly Patients ◽  
Cell Viability ◽  
Cell Lines ◽  
Protein Turnover ◽  
Cell Cycle Progression ◽  
Clonogenic Survival ◽  
Cycle Progression

Abstract Abstract 3255 Cytarabine-based therapy has been utilized in acute myeloid leukemia (AML) therapy for more than 30 years. However, the complete response (CR) rates are markedly inferior in older compared to younger patients with AML (45% versus 75%, respectively) due, in part, to the reduced ability of elderly patients to tolerate intensive therapy. Improving the outcomes for patients treated with cytarabine-based regimens represents a major clinical challenge in this disease. A randomized study of elderly patients with AML demonstrated that low dose cytarabine (LDAC) is superior to best supportive care. However, this regimen was not associated with any CRs in patients with adverse karyotype disease and/or poor baseline performance scores. Novel approaches are urgently needed to increase the efficacy of LDAC therapy for these patients. Timed protein destruction plays a crucial role in cellular homeostasis and is essential for many critical functions including cell cycle progression, signal transduction, and apoptosis. The processes that govern protein degradation frequently become dysregulated in cancer cells. Aberrant protein turnover contributes to disease progression, metastasis, and therapeutic resistance and therefore is an attractive target for selective pharmacological inhibition. The cullin-RING ubiquitin ligases (CRLs) are a subset of E3 ubiquitin ligases whose activity is regulated by modification with the ubiquitin-like molecule NEDD8. The CRLs control the ubiquitination and subsequent degradation of many proteins with important roles in cell cycle progression, DNA damage, stress responses, and signal transduction. MLN4924 is a potent and selective small molecule inhibitor of NEDD8 activating enzyme (NAE), the proximal regulator of the NEDD8 conjugation pathway, and has entered Phase I clinical trials for AML and other forms of cancer. Our earlier preclinical studies demonstrated that MLN4924 induced cell death in AML cell lines and primary patient specimens independent of FLT3 expression and stromal-mediated survival signaling and led to the stabilization of key NAE targets, inhibition of NF-kB activity, DNA damage, and reactive oxygen species generation. Notably, administration of MLN4924 to mice bearing AML xenografts was very well tolerated, led to stable disease regression and inhibition of NEDDylated cullins. Based on the high tolerability, potency, and multifaceted mechanism of action of MLN4924, we hypothesized that it may significantly augment the efficacy of the standard agent cytarabine. To test our hypothesis, we first investigated the effects of this therapeutic combination on cell viability, clonogenic survival, and apoptosis induction in a panel of AML cell lines. MLN4924 cooperated with cytarabine to significantly reduce cell viability, inhibit clonogenic survival, and induce mitochondrial-dependent apoptosis. The addition of MLN4924 did not significantly alter the sensitivity of normal peripheral blood mononuclear cells from healthy donors to cytarabine, indicating that this combination may have therapeutic selectivity. Immunoblotting analyses revealed that MLN4924 enhanced cytarabine-induced stabilization of the NEDD8 target and cell cycle regulator, p27. The MLN4924/cytarabine combination also promoted increased phosphorylation of the DNA damage response regulator Chk1. Targeted knockdown of Chk1 demonstrated a critical role for Chk1 as a mediator of the pro-apoptotic effects of this combination. In vivo examining the combination is in progress and will be presented. Our collective findings suggest that combining the novel NAE inhibitor MLN4924 with cytarabine is a promising strategy for AML therapy that warrants further investigation. Disclosures: Smith: Millennium Pharmaceuticals, Inc.: Employment.

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 A Syx-RhoA-Dia1 signaling axis regulates cell cycle progression, DNA damage, and therapy resistance in glioblastoma

2021 ◽  
Author(s):  
Wan-Hsin Lin ◽  
Ryan W. Feathers ◽  
Lisa M. Cooper ◽  
Laura J. Lewis-Tuffin ◽  
Jann N. Sarkaria ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Progression ◽  
Radiation Treatment ◽  
Therapy Resistance ◽  
Cell Cycle Regulators ◽  
Nucleotide Exchange ◽  
M Cell ◽  
Cycle Progression ◽  
Signaling Axis

AbstractGlioblastomas (GBM) are aggressive tumors that lack effective treatments. Here, we show that the Rho family guanine nucleotide exchange factor Syx promotes GBM cell growth both in vitro and in orthotopic GBM patient-derived xenografts. Growth defects upon Syx depletion are attributed to prolonged mitosis, increased DNA damage, G2/M cell cycle arrest, and cell apoptosis, mediated by altered mRNA and protein expression of various cell cycle regulators. These effects are phenocopied by depletion of the Rho downstream effector Dia1 and are due at least in part to increased cytoplasmic retention and reduced activity of the YAP/TAZ transcriptional coactivators. Further, targeting Syx signaling cooperates with radiation treatment and temozolomide (TMZ) to decrease viability in GBM cells irrespective of their inherent response to TMZ. Taken together, the data indicate that a Syx-RhoA-Dia1-YAP/TAZ signaling axis regulates cell cycle progression, DNA damage, and therapy resistance in GBM and argue for its targeting for cancer treatment.One Sentence SummarySyx promotes growth and therapy resistance in glioblastoma.

scholarly journals Sensitivity of cells to ATR and CHK1 inhibitors requires hyperactivation of CDK2 rather than endogenous replication stress or ATM dysfunction

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jennifer P. Ditano ◽  
Katelyn L. Donahue ◽  
Laura J. Tafe ◽  
Charlotte F. McCleery ◽  
Alan Eastman
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
Single Agent ◽  
Replication Stress ◽  
Cell Cycle Checkpoint ◽  
High Threshold ◽  
Cycle Checkpoint ◽  
Atm Signaling

AbstractDNA damage activates cell cycle checkpoint proteins ATR and CHK1 to arrest cell cycle progression, providing time for repair and recovery. Consequently, inhibitors of ATR (ATRi) and CHK1 (CHK1i) enhance damage-induced cell death. Intriguingly, both CHK1i and ATRi alone elicit cytotoxicity in some cell lines. Sensitivity has been attributed to endogenous replications stress, but many more cell lines are sensitive to ATRi than CHK1i. Endogenous activation of the DNA damage response also did not correlate with drug sensitivity. Sensitivity correlated with the appearance of γH2AX, a marker of DNA damage, but without phosphorylation of mitotic markers, contradicting suggestions that the damage is due to premature mitosis. Sensitivity to ATRi has been associated with ATM mutations, but dysfunction in ATM signaling did not correlate with sensitivity. CHK1i and ATRi circumvent replication stress by reactivating stalled replicons, a process requiring a low threshold activity of CDK2. In contrast, γH2AX induced by single agent ATRi and CHK1i requires a high threshold activity CDK2. Hence, phosphorylation of different CDK2 substrates is required for cytotoxicity induced by replication stress plus ATRi/CHK1i as compared to their single agent activity. In summary, sensitivity to ATRi and CHK1i as single agents is elicited by premature hyper-activation of CDK2.

scholarly journals Inhibition of PIM Kinases Mitigates DNA Repair Responses Following Anthracycline-Induced DNA Damage and Enhances the Anti-Tumor Activity of Doxorubicin Against Lymphoma Cells

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4505-4505 ◽  
Author(s):  
Jeffrey D. Altenburg ◽  
Shuhong Zhang ◽  
Michelle Grimard ◽  
Xingkui Xue ◽  
Sherif S Farag
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Death ◽  
Dna Repair ◽  
Cell Growth ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
Fold Increase ◽  
Pim Kinases ◽  
Anti Cancer

Abstract The PIM kinases are a family of proteins recently identified as promising therapeutic targets in several cancers, including pancreatic, B-cell malignancies, acute leukemia, and prostate cancer among others. The family of PIM kinases is composed of three different members (PIM-1, -2, and -3) that are short-lived serine/threonine kinases involved in the regulation of a number of cellular pathways that are important for cancer cell growth and survival. The PIM kinases show high homology with each other, and exhibit functional redundancy in vitro and in vivo. Overexpression of PIM kinases promotes tumor growth through activation of several key cell-cycle progression and anti-apoptotic proteins, including BAD, p21, p27KIP, c-Myc, and AKT-1. Recently, overexpression of PIM-2 has been shown to have a protective effect against ultraviolet light induced DNA damage (Zirkin et al. J Biol Chem288:21770-83, 2013). We investigated the protective role of PIM kinases in chemotherapy-induced DNA damage, and whether inhibition of PIM kinases enhances anthracycline-induced DNA damage by inhibiting DNA repair, thus enhancing cell death in lymphoma cells lines. Using immunobloting and RT-PCR, we found similarly low levels of PIM-1 and PIM-3, but a wide range of PIM-2 expression, in a panel of non-Hodgkin lymphoma (NHL) cell lines, including Raji, HS Sultan, Daudi, Farage, Granta519, and Toledo. Treatment of cells with doxorubicin (200-400 nM) resulted in up to a five fold increase gene transcription and expression of PIM-1 and PIM-2, which was maximal at 6 hours, and was associated with an increase in DNA damage as detected using acridine orange flow cytometry assay. We also tested the single agent effect of the pan-PIM kinase inhibitor, CX6258 on the cell lines. CX6258 alone inhibited cell growth in all NHL cell lines with varying degrees of potency with IC50ranging from 0.2 – 12.9 µM. The anti-cancer was associated most with PIM-2 expression, with the most sensitive cell lines, Daudi and Toledo, expressing the most PIM-2. Suppression of PIM-2 expression by shRNA significantly decreased proliferation, indicating that PIM-2 is a significant factor in cell growth. Treatment of NHL cells with CX6258 resulted in increased caspase-3 activation and PARP cleavage, decreased BAD phosphorylation, and apoptosis. Treatment with CX6258 also increased expression of p21, decreased expression of cyclins A1 and B1, and induced G2-M cell cycle arrest. The effect of combinations of CX6258 (5-50 µM) and doxorubicin (50-500 nM) on DNA damage and cell death was tested on HS sultan and Daudi cells. While doxorubicin alone resulted in a two-fold increase in DNA damage, this was significantly increased in the presence of CX6258 (12 fold). The addition of CX6258 inhibited the phosphorylation of the DNA repair proteins H2.AX, ATM, and Chk2 that occurred when the cells were treated with doxorubicin alone. The combination of CX6258 and doxorubicin was synergistic in inducing lymphoma cell death, with combination indexes ranging from 0.32-0.85. Our findings suggest a mechanism for synergy where doxorubicin damages cellular DNA and initiates the DNA damage response, while CX6258 inhibits the upregulated PIM kinases from activating the proteins involved in the response. This synergistic anti-tumor activity is further strengthened by the CX6258 inhibition of cell cycle progression and anti-apoptotic proteins activated by the PIM kinases. Taken together, our results provide pre-clinical rationale for clinical testing of PIM kinase inhibitors in combination with doxorubicin in patients with NHL. It also suggests that CX6258 may similarly enhance the anti-cancer effects of other DNA damaging agents. Disclosures No relevant conflicts of interest to declare.

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 Regulation of Cell Division in Bacteria by Monitoring Genome Integrity and DNA Replication Status

2019 ◽  
Vol 202 (2) ◽  
Author(s):  
Peter E. Burby ◽  
Lyle A. Simmons
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Division ◽  
Dna Replication ◽  
Cell Cycle Progression ◽  
Genome Instability ◽  
Sos Response ◽  
Bacterial Cells ◽  
Cycle Progression ◽  
Content Type

ABSTRACT All organisms regulate cell cycle progression by coordinating cell division with DNA replication status. In eukaryotes, DNA damage or problems with replication fork progression induce the DNA damage response (DDR), causing cyclin-dependent kinases to remain active, preventing further cell cycle progression until replication and repair are complete. In bacteria, cell division is coordinated with chromosome segregation, preventing cell division ring formation over the nucleoid in a process termed nucleoid occlusion. In addition to nucleoid occlusion, bacteria induce the SOS response after replication forks encounter DNA damage or impediments that slow or block their progression. During SOS induction, Escherichia coli expresses a cytoplasmic protein, SulA, that inhibits cell division by directly binding FtsZ. After the SOS response is turned off, SulA is degraded by Lon protease, allowing for cell division to resume. Recently, it has become clear that SulA is restricted to bacteria closely related to E. coli and that most bacteria enforce the DNA damage checkpoint by expressing a small integral membrane protein. Resumption of cell division is then mediated by membrane-bound proteases that cleave the cell division inhibitor. Further, many bacterial cells have mechanisms to inhibit cell division that are regulated independently from the canonical LexA-mediated SOS response. In this review, we discuss several pathways used by bacteria to prevent cell division from occurring when genome instability is detected or before the chromosome has been fully replicated and segregated.

scholarly journals Acceleration or Brakes: Which Is Rational for Cell Cycle-Targeting Neuroblastoma Therapy?

Biomolecules ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 750
Author(s):  
Kiyohiro Ando ◽  
Akira Nakagawara
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Progression ◽  
Parp Inhibitors ◽  
Cell Cycle Checkpoint ◽  
Mitotic Catastrophe ◽  
Malignant Neoplasms ◽  
Checkpoint Kinases ◽  
Molecular Features ◽  
Cycle Checkpoint

Unrestrained proliferation is a common feature of malignant neoplasms. Targeting the cell cycle is a therapeutic strategy to prevent unlimited cell division. Recently developed rationales for these selective inhibitors can be subdivided into two categories with antithetical functionality. One applies a “brake” to the cell cycle to halt cell proliferation, such as with inhibitors of cell cycle kinases. The other “accelerates” the cell cycle to initiate replication/mitotic catastrophe, such as with inhibitors of cell cycle checkpoint kinases. The fate of cell cycle progression or arrest is tightly regulated by the presence of tolerable or excessive DNA damage, respectively. This suggests that there is compatibility between inhibitors of DNA repair kinases, such as PARP inhibitors, and inhibitors of cell cycle checkpoint kinases. In the present review, we explore alterations to the cell cycle that are concomitant with altered DNA damage repair machinery in unfavorable neuroblastomas, with respect to their unique genomic and molecular features. We highlight the vulnerabilities of these alterations that are attributable to the features of each. Based on the assessment, we offer possible therapeutic approaches for personalized medicine, which are seemingly antithetical, but both are promising strategies for targeting the altered cell cycle in unfavorable neuroblastomas.

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