scholarly journals Inhibitors of the VEGF Receptor Suppress HeLa S3 Cell Proliferation via Misalignment of Chromosomes and Rotation of the Mitotic Spindle, Causing a Delay in M-Phase Progression

2018 ◽  
Vol 19 (12) ◽  
pp. 4014 ◽  
Author(s):  
Daiki Okumura ◽  
Mari Hagino ◽  
Akane Yamagishi ◽  
Yuichiro Kaibori ◽  
Sirajam Munira ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Mitotic Spindle ◽  
Spindle Assembly Checkpoint ◽  
Phase Delay ◽  
Vegf Receptor ◽  
Dependent Manner ◽  
M Phase ◽  
Hela S3 ◽  
Phase Progression ◽  
Suppress Cell Proliferation

Cell division is the process by which replicated chromosomes are separated into two daughter cells. Although regulation of M phase has been extensively investigated, not all regulating factors have been identified. Over the course of our research, small molecules were screened to identify those that regulate M phase. In the present study, the vascular endothelial growth factor receptor (VEGFR) inhibitors A83-01, SU4312, and Ki8751 were examined to determine their effects on M phase. Treatment of HeLa S3 cells with these inhibitors suppressed cell proliferation in a concentration-dependent manner, and also suppressed Akt phosphorylation at Ser473, a marker of Akt activation. Interestingly, cleaved caspase-3 was detected in Adriamycin-treated cells but not in inhibitor-treated cells, suggesting that these inhibitors do not suppress cell proliferation by causing apoptosis. A cell cycle synchronization experiment showed that these inhibitors delayed M phase progression, whereas immunofluorescence staining and time-lapse imaging revealed that the M phase delay was accompanied by misalignment of chromosomes and rotation of the mitotic spindle. Treatment with the Mps1 inhibitor AZ3146 prevented the SU4312-induced M phase delay. In conclusion, the VEGFR inhibitors investigated here suppress cell proliferation by spindle assembly checkpoint-induced M phase delay, via misalignment of chromosomes and rotation of the mitotic spindle.

scholarly journals ALK Inhibitors-Induced M Phase Delay Contributes to the Suppression of Cell Proliferation

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 1054
Author(s):  
Sirajam Munira ◽  
Ryuzaburo Yuki ◽  
Youhei Saito ◽  
Yuji Nakayama
Keyword(s):  
Cell Proliferation ◽  
Spindle Assembly Checkpoint ◽  
Time Lapse ◽  
Phase Delay ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Alk Inhibitors ◽  
Anaplastic Lymphoma ◽  
Monopolar Spindle ◽  
M Phase

Anaplastic lymphoma kinase (ALK), a receptor-type tyrosine kinase, is involved in the pathogenesis of several cancers. ALK has been targeted with small molecule inhibitors for the treatment of different cancers, but absolute success remains elusive. In the present study, the effects of ALK inhibitors on M phase progression were evaluated. Crizotinib, ceritinib, and TAE684 suppressed proliferation of neuroblastoma SH-SY5Y cells in a concentration-dependent manner. At approximate IC50 concentrations, these inhibitors caused misorientation of spindles, misalignment of chromosomes and reduction in autophosphorylation. Similarly, knockdown of ALK caused M phase delay, which was rescued by re-expression of ALK. Time-lapse imaging revealed that anaphase onset was delayed. The monopolar spindle 1 (MPS1) inhibitor, AZ3146, and MAD2 knockdown led to a release from inhibitor-induced M phase delay, suggesting that spindle assembly checkpoint may be activated in ALK-inhibited cells. H2228 human lung carcinoma cells that express EML4-ALK fusion showed M phase delay in the presence of TAE684 at about IC50 concentrations. These results suggest that ALK plays a role in M phase regulation and ALK inhibition may contribute to the suppression of cell proliferation in ALK-expressing cancer cells.

Fyn Accelerates M Phase Progression by Promoting the Assembly of Mitotic Spindle Microtubules

2015 ◽  
Vol 117 (4) ◽  
pp. 894-903 ◽  
Author(s):  
Mai Okamoto ◽  
Yuji Nakayama ◽  
Ayana Kakihana ◽  
Ryuzaburo Yuki ◽  
Noritaka Yamaguchi ◽  
...  
Keyword(s):  
Mitotic Spindle ◽  
M Phase ◽  
Phase Progression ◽  
Spindle Microtubules

Effect of Metformin Intervention on Pancreatic β-Cell Apoptosis

2022 ◽  
Vol 12 (4) ◽  
pp. 873-877
Author(s):  
Dongqian Xie ◽  
Zhicheng Gao ◽  
Mei Liu ◽  
Defeng Wang
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Cell Apoptosis ◽  
Dependent Manner ◽  
Cycle Arrest ◽  
High Glucose Condition ◽  
M Phase ◽  
Signaling Activation

Metformin is shown to have hypoglycemic effects. However, the relationship between metformin’s intervention in FFA-induced endoplasmic reticulum stress-mediated insulin resistance (IR) and insulin β-cell apoptosis under high-glucose condition remains unclear. Our study intends to assess their relationship. Human pancreatic β-cells were treated with metformin and cell proliferation and IR were detected by MTT assay along with detection of Wnt/β-catenin signaling by RT-PCR, cell cycle and apoptosis by flow cytometry. Metformin inhibited β cell proliferation which was mediated by FFA-induced endoplasmic reticulum stress in a time-dependent and dose-dependent manner as well as induced cell cycle arrest at G2/M phase. In addition, metformin inhibited β-catenin signaling activation and decreased the expression of c-myc, Dvl-2, survivin, Dvl-3, GSK-3β (p-ser9) and promoted GSK-3 (p-tyr216) and Axin-2 expression. In conclusion, metformin inhibits Wnt/β-catenin signaling and promotes FFA to induce endoplasmic reticulum stress, thereby mediating pancreatic β-cells behaviors.

Ex Vivo Anti-Tumor Activity of Rosiglitazone on Multiple Myeloma Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5052-5052 ◽  
Author(s):  
Haiwen Huang ◽  
De Pei Wu ◽  
Anskar Y.H. Leung ◽  
Raymond Liang ◽  
Albert K.W. Lie
Keyword(s):  
Cell Proliferation ◽  
Caspase 3 ◽  
Hormone Receptors ◽  
Ex Vivo ◽  
Survivin Expression ◽  
Myeloma Cell ◽  
Dependent Manner ◽  
Novel Therapy ◽  
Apoptosis Protein ◽  
M Phase

Abstract Peroxisome proliferation activated receptor-g (PPAR-g) belongs to the family of nuclear hormone receptors (NHRs), it is normally expressed in adipocytes, adrenal gland, spleen and liver. Recently it was reported that PPAR-g can also be found in tumor tissues. Activation of PPAR-g by its ligands has potential anti-neoplastic effects in a variety of human malignancies, including leukemia through inhibition of cell proliferation, induction of apoptosis and terminal differentiation. The ligands of PPAR-g may represent a promising, novel therapeutic approach for certain human malignancies. The thiazolidinedione (TZD) class drug rosiglitazone (RGZ), one of synthetic ligands of PPAR-g, is currently used for the treatment of type 2 diabetes. In this study, we cultured myeloma cell line U266 with different concentration of rosiglitazone, as well as combined with dexamethasone. Cell proliferation was measured by [3H] thymidine incorporation after 48h incubation. Rosiglitazone was found to generate inhibition of cell proliferation on U266 cells in a dose-dependent manner. Cell cycle analysis by flow cytometry showed that rosiglitazone can arrested U266 cells in G0/G1 phase and the G2/M phase cells were significantly decreased compared to controls. We also studied the effect of rosiglitazone on expression of different anti-apoptosis protein FLIP and survivin by RT-PCR, the result revealed that rosiglitazone can also decrease the FLIP and survivin expression. Furthermore, exposure to rosiglitazone can induce the decreased caspase-3 activity in U266 cells, which was associated with apoptosis induction. When rosiglitazone was combined with dexamethasone, the data demonstrated that cell growth inhibition and apoptosis they exerted was much greater than they were used alone, the decreased expression of FLIP and survivin and decreased caspase-3 activity were also greater than when rosiglitazone was used alone. Based on these findings, we suppose that rosiglitazone alone and in combination with dexamethasone holds promise as novel therapy for myeloma.

20(S)-Ginsenoside Rg3 Inhibits Human Glioma Cell Growth through the Suppression of Voltage-Gated K+ Channels

2014 ◽  
Vol 998-999 ◽  
pp. 160-163
Author(s):  
Qin Ru ◽  
Xiang Tian ◽  
Yu Xiang Wu ◽  
Kai Yue ◽  
Lin Chen ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Underlying Mechanism ◽  
Control Group ◽  
Dependent Manner ◽  
Human Glioma ◽  
Voltage Gated ◽  
New Findings ◽  
Proliferation And Apoptosis ◽  
M Phase ◽  
Channel Currents

Previous studies demonstrated that 20(S)-ginsenoside Rg3 (20S-Rg3) could effectively inhibit tumor cell proliferation as well as K+ channel currents expressed in xenopus oocytes. However, the effect of 20S-Rg3 on the growth of human glioma cells and the ion channels expressed in tumor cells was rarely reported in the literature. In the present study, we investigated the effect and the underlying mechanism of 20S-Rg3 on cell proliferation and apoptosis of human glioma U87-MG cells. In vitro results exhibited that 20S-Rg3 had potent cytotoxic effect and significantly inhibited the proliferation of U87-MG cells in a dose-and time-dependent manner. Typical arrest at G2/M phase was induced, and the apoptosis rate of U87-MG cells was significantly higher in the 20S-Rg3 treatment group than in the control group. Electrophysiological results showed that 80 μmol/L 20S-Rg3 substantially inhibited voltage-gated K+ currents of U87-MG cells. Together, these results suggest that the suppression of voltage-gated K+ currents might play an important role in the 20S-Rg3-induced cell death, and these new findings provide useful data for further study of the antitumor effect of 20S-Rg3.

scholarly journals Cdc7 kinase stimulates Aurora B kinase in M-phase

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Sayuri Ito ◽  
Hidemasa Goto ◽  
Kinue Kuniyasu ◽  
Mayumi Shindo ◽  
Masayuki Yamada ◽  
...  
Keyword(s):  
Spindle Assembly Checkpoint ◽  
Kinase Activity ◽  
Phosphorylation Site ◽  
Aurora B ◽  
Aurora B Kinase ◽  
Mitotic Kinase ◽  
M Phase ◽  
Phase Progression ◽  
Autophosphorylation Site

AbstractThe conserved serine-threonine kinase, Cdc7, plays a crucial role in initiation of DNA replication by facilitating the assembly of an initiation complex. Cdc7 is expressed at a high level and exhibits significant kinase activity not only during S-phase but also during G2/M-phases. A conserved mitotic kinase, Aurora B, is activated during M-phase by association with INCENP, forming the chromosome passenger complex with Borealin and Survivin. We show that Cdc7 phosphorylates and stimulates Aurora B kinase activity in vitro. We identified threonine-236 as a critical phosphorylation site on Aurora B that could be a target of Cdc7 or could be an autophosphorylation site stimulated by Cdc7-mediated phosphorylation elsewhere. We found that threonines at both 232 (that has been identified as an autophosphorylation site) and 236 are essential for the kinase activity of Aurora B. Cdc7 down regulation or inhibition reduced Aurora B activity in vivo and led to retarded M-phase progression. SAC imposed by paclitaxel was dramatically reversed by Cdc7 inhibition, similar to the effect of Aurora B inhibition under the similar situation. Our data show that Cdc7 contributes to M-phase progression and to spindle assembly checkpoint most likely through Aurora B activation.

scholarly journals Targeting Insulin-Like Growth Factor 1 Receptor Delays M-Phase Progression and Synergizes with Aurora B Inhibition to Suppress Cell Proliferation

2020 ◽  
Vol 21 (3) ◽  
pp. 1058
Author(s):  
Akane Yamagishi ◽  
Yuki Ikeda ◽  
Masayoshi Ikeuchi ◽  
Ryuzaburo Yuki ◽  
Youhei Saito ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Growth Factor ◽  
Cancer Progression ◽  
Spindle Assembly Checkpoint ◽  
Aurora B ◽  
Insulin Like Growth Factor ◽  
Altered Expression ◽  
M Phase ◽  
Igf1r Inhibitor ◽  
The Impact

The insulin-like growth factor 1 receptor (IGF1R) is a receptor-type tyrosine kinase that transduces signals related to cell proliferation, differentiation, and survival. IGF1R expression is often misregulated in tumor cells, but the relevance of this for cancer progression remains unclear. Here, we examined the impact of IGF1R inhibition on cell division. We found that siRNA-mediated knockdown of IGF1R from HeLa S3 cells leads to M-phase delays. Although IGF1R depletion causes partial exclusion of FoxM1 from the nucleus, quantitative real-time PCR revealed that the transcription of M-phase regulators is not affected by decreased levels of IGF1R. Moreover, a similar delay in M phase was observed following 2 h of incubation with the IGF1R inhibitors OSI-906 and NVP-ADW742. These results suggest that the M-phase delay observed in IGF1R-compromised cells is not caused by altered expression of mitotic regulators. Live-cell imaging revealed that both prolonged prometaphase and prolonged metaphase underlie the delay and this can be abrogated by the inhibition of Mps1 with AZ3146, suggesting activation of the Spindle Assembly Checkpoint when IGF1R is inhibited. Furthermore, incubation with the Aurora B inhibitor ZM447439 potentiated the IGF1R inhibitor-induced suppression of cell proliferation, opening up new possibilities for more effective cancer chemotherapy.

scholarly journals The BUBR1 pseudokinase domain promotes efficient kinetochore PP2A-B56 recruitment to regulate spindle checkpoint silencing and chromosome alignment

2019 ◽  
Author(s):  
Luciano Gama Braga ◽  
Angel F. Cisneros ◽  
Michelle Mathieu ◽  
Maxime Clerc ◽  
Pauline Garcia ◽  
...  
Keyword(s):  
Mitotic Spindle ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Aurora B ◽  
Dependent Manner ◽  
Regulatory Domain ◽  
Checkpoint Protein ◽  
Major Player ◽  
Chromosome Alignment ◽  
Spindle Assembly Checkpoint Protein

ABSTRACTThe balance of phospho-signalling at outer-kinetochores during mitosis is critical for the accurate attachments between kinetochores and the mitotic spindle and timely exit from mitosis. In humans, a major player in determining this balance is the PP2A-B56 phosphatase which is recruited to the Kinase Attachment Regulatory Domain (KARD) of the Spindle Assembly Checkpoint protein Budding Uninhibited by Benzimidazole 1-related 1 (BUBR1) in a phospho-dependent manner. This event unleashes a rapid, switch-like phosphatase relay that reverses phosphorylation at the kinetochore, extinguishing the checkpoint and promoting anaphase entry. Here, we conclusively demonstrate that the pseudokinase domain of human BUBR1 lacks phosphotransfer activity and that it was maintained in vertebrates because it allosterically promotes KARD phosphorylation. Mutation or removal of this domain results in decreased PP2A-B56 recruitment to the outer kinetochore, attenuated checkpoint silencing and errors in chromosome alignment as a result of imbalance in Aurora B activity. We demonstrate that the functions of the BUBR1 pseudokinase and the BUB1 kinase domains are intertwined, providing an explanation for retention of the pseudokinase domain in certain eukaryotes.

scholarly journals Myc/Max dependent intronic long antisense noncoding RNA, EVA1A-AS, suppresses the expression of Myc/Max dependent anti-proliferating gene EVA1A in a U2 dependent manner

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Svenja E. Niehus ◽  
Aldrige B. Allister ◽  
Andrea Hoffmann ◽  
Lutz Wiehlmann ◽  
Teruko Tamura ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Noncoding Rna ◽  
Patient Survival ◽  
Normal Liver ◽  
Dependent Manner ◽  
Expression Levels ◽  
Large Numbers ◽  
M Phase ◽  
Myc Gene

AbstractThe Myc gene has been implicated in the pathogenesis of most types of human cancerous tumors. Myc/Max activates large numbers of pro-tumor genes; however it also induces anti-proliferation genes. When anti-proliferation genes are activated by Myc, cancer cells can only survive if they are downregulated. Hepatocellular carcinoma (HCC) specific intronic long noncoding antisense (lnc-AS) RNA, the EVA1A-AS gene, is located within the second intron (I2) of the EVA1A gene (EVA-1 homolog A) that encodes an anti-proliferation factor. Indeed, EVA1A, but not EVA1A-AS, is expressed in normal liver. Depletion of EVA1A-AS suppressed cell proliferation of HepG2 cells by upregulation of EVA1A. Overexpression of EVA1A caused cell death at the G2/M phase via microtubule catastrophe. Furthermore, suppressed EVA1A expression levels are negatively correlated with differentiation grade in 365 primary HCCs, while EVA1A-AS expression levels are positively correlated with patient survival. Notably, both EVA1A and EVA1A-AS were activated by the Myc/Max complex. Eva1A-AS is transcribed in the opposite direction near the 3′splice site of EVA1A I2. The second intron did not splice out in a U2 dependent manner and EVA1A mRNA is not exported. Thus, the Myc/Max dependent anti-proliferating gene, EVA1A, is controlled by Myc/Max dependent anti-sense noncoding RNA for HCC survival.

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