SKLB70326, a novel small-molecule inhibitor of cell-cycle progression, induces G0/G1 phase arrest and apoptosis in human hepatic carcinoma cells

2012 ◽  
Vol 421 (4) ◽  
pp. 684-689 ◽  
Author(s):  
Yuanyuan Han ◽  
Haiyun He ◽  
Feng Peng ◽  
Jiyan Liu ◽  
Xiaoyun Dai ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Small Molecule ◽  
Cell Cycle Progression ◽  
Carcinoma Cells ◽  
G1 Phase ◽  
Hepatic Carcinoma ◽  
Cycle Progression ◽  
Phase Arrest ◽  
Molecule Inhibitor ◽  
G1 Phase Arrest

scholarly journals Icariin affects cell cycle progression and proliferation of human retinal pigment epithelial cells via enhancing expression of H19

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e8830
Author(s):  
Yibing Zhang ◽  
Min Li ◽  
Xue Han
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Cycle Progression ◽  
Retinal Pigment Epithelial ◽  
Retinal Pigment ◽  
Inhibitory Effects ◽  
Cycle Progression ◽  
Rpe Cells ◽  
Phase Arrest ◽  
G1 Phase Arrest

Background Aberrant proliferation of retinal pigment epithelial (RPE) cells under pathologic condition results in the occurrence of proliferative vitreoretinopathy (PVR). Icariin (ICA)-a flavonol glucoside-has been shown to inhibit proliferation of many cell types, but the effect on RPE cells is unknown. This study aimed to clarify the inhibitory effects of ICA on RPE cells against platelet-derived growth factor (PDGF)-BB-induced cell proliferation, and discuss the regulatory function of H19 in RPE cells. Methods MTS assay was conducted to determine the effects of ICA on cell proliferation. Flow cytometry analysis was performed to detect cell cycle progression. Quantitative real-time PCR and western blot assay were used to measure the expression patterns of genes in RPE cells. Results ICA significantly suppressed PDGF-BB-stimulated RPE cell proliferation in a concentration-dependent manner. Moreover, since administration of ICA induced cell cycle G0/G1 phase arrest, the anti-proliferative activity of ICA may be due to G0/G1 phase arrest in RPE cells. At molecular levels, cell cycle regulators cyclin D1, CDK4, CDK6, p21 and p53 were modulated in response to treatment with ICA. Most importantly, H19 was positively regulated by ICA and H19 depletion could reverse the inhibitory effects of ICA on cell cycle progression and proliferation in PDGF-BB-stimulated RPE cells. Further mechanical explorations showed that H19 knockdown resulted in alternative expressions levels of cyclin D1, CDK4, CDK6, p21 and p53 under ICA treatment. Conclusions Our findings revealed that ICA was an effective inhibitor of PDGF-BB-induced RPE cell proliferation through affecting the expression levels of cell cycle-associated factors, and highlighted the potential application of ICA in PVR therapy. H19 was described as a target regulatory gene of ICA whose disruption may contribute to excessive proliferation of RPE cells, suggesting that modulation of H19 expression may be a novel therapeutic approach to treat PVR.

scholarly journals CCNE1 and E2F1 Partially Suppress G1 Phase Arrest Caused by Spliceostatin A Treatment

2021 ◽  
Vol 22 (21) ◽  
pp. 11623
Author(s):  
Kei Kikuchi ◽  
Daisuke Kaida
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Kinase Inhibitor ◽  
G1 Phase ◽  
Cell Cycle Regulators ◽  
Protein Levels ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Phase Arrest ◽  
G1 Phase Arrest ◽  
Spliceostatin A

The potent splicing inhibitor spliceostatin A (SSA) inhibits cell cycle progression at the G1 and G2/M phases. We previously reported that upregulation of the p27 cyclin-dependent kinase inhibitor encoded by CDKN1B and its C-terminal truncated form, namely p27*, which is translated from CDKN1B pre-mRNA, is one of the causes of G1 phase arrest caused by SSA treatment. However, the detailed molecular mechanism underlying G1 phase arrest caused by SSA treatment remains to be elucidated. In this study, we found that SSA treatment caused the downregulation of cell cycle regulators, including CCNE1, CCNE2, and E2F1, at both the mRNA and protein levels. We also found that transcription elongation of the genes was deficient in SSA-treated cells. The overexpression of CCNE1 and E2F1 in combination with CDKN1B knockout partially suppressed G1 phase arrest caused by SSA treatment. These results suggest that the downregulation of CCNE1 and E2F1 contribute to the G1 phase arrest induced by SSA treatment, although they do not exclude the involvement of other factors in SSA-induced G1 phase arrest.

MLN4924, A Novel First in Class Small Molecule Inhibitor of the Nedd8 Activating Enzyme (NAE), Has Potent Activity in Preclinical Models of Acute Myeloid Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1021-1021
Author(s):  
Ronan T. Swords ◽  
Kevin R. Kelly ◽  
Peter G. Smith ◽  
James J. Gansey ◽  
Devalingam Mahalingam ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Death ◽  
Acute Myeloid Leukemia ◽  
Small Molecule ◽  
Myeloid Leukemia ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Molecule Inhibitor ◽  
Acute Myeloid

Abstract Abstract 1021 Poster Board I-43 The coordinated balance between the synthesis and degradation of proteins is an important regulator of cancer cell biology. The ubiquitin-proteasome system (UPS) is responsible for the timed destruction of many proteins including key mediators of fundamental signaling cascades and critical regulators of cell cycle progression and transcription. Within the UPS, the E3 ligases are multi-protein complexes whose specificity is established by their individual components as well as post-translational modifications by various factors including the ubiquitin-like molecule, Nedd8. The Nedd8 activating enzyme (NAE) has been identified as an essential regulator of the Nedd8 conjugation pathway, which controls the activity of the cullin-dependent E3 ubiquitin ligases. The cullins direct the ubiquitination and subsequent degradation of many proteins with important roles in cell cycle progression (p27, cyclin E), DNA damage (Cdt-1), stress response (NRF-2, HIF1α) and signal transduction (IκBα). Acute myeloid leukemia (AML) is a disease of the elderly and prognosis is extremely poor with a median overall survival of just 2 months for untreated patients. As such, novel therapeutic strategies are urgently needed to improve clinical outcomes. Considering that Nedd8-mediated control of protein homeostasis is vitally important for the survival of AML cells, we hypothesized that disrupting this process would inhibit proliferation and induce cell death. We tested this hypothesis by investigating the preclinical anti-leukemic activity of MLN4924, a novel first in class small molecule inhibitor of the Nedd8 activating enzyme. MLN4924 induced DNA damage followed by rapid and selective caspase-dependent cell death in AML cell lines and primary AML cells from patients, but not in peripheral blood mononuclear cells from healthy donors. Transient exposure to MLN4924 impaired colony formation in a dose-dependent manner. Kinetic analysis of drug-induced effects on cell cycle distribution revealed that AML cells treated with MLN4924 initially arrested at the G1 transition prior to their subsequent accumulation in the sub-G1 compartment. Assays conducted using MV-411 cells with and without stable shRNA-mediated knockdown of FLT3 expression demonstrated that MLN4924 is highly effective independent of FLT3 status. Further investigation revealed that the activity of MLN4924 was preserved when cells were co-cultured with bone marrow stromal cells indicating that it has the ability to overcome the effects of stromal-mediated survival signaling that has been established to blunt the efficacy of relevant standard of care agents. MLN4924 induced a dose and time dependant increase in the expression of phospo-IκB, an important target for degradation through the Nedd8 conjugation pathway. The inhibitory effects of MLN4924 on NFκB were confirmed by demonstrating that the transcriptional activity of the NFκB p65 subunit was significantly reduced following drug exposure. Moreover, treatment of immunodeficient mice implanted with HL-60 human leukemia cells with MLN4924 led to an inhibition of neddylated cullins, accumulation of phospho-IκBα and achieved complete and stable disease regression. Our results indicate that MLN4924 is a highly promising novel agent for the treatment of AML and warrants further evaluation in clinical trials. Disclosures: Smith: Millennium Pharmaceuticals: Employment. Gansey:Millennium Pharmaceuticals: Employment.

Interactions of Vascular Endothelial Growth Factor and p53 with miR-195 in Thyroid Carcinoma: Possible Therapeutic Targets in Aggressive Thyroid Cancers

2019 ◽  
Vol 19 (7) ◽  
pp. 561-570 ◽  
Author(s):  
Hamidreza Maroof ◽  
Soussan Irani ◽  
Armin Arianna ◽  
Jelena Vider ◽  
Vinod Gopalan ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Thyroid Carcinoma ◽  
Cell Cycle Progression ◽  
P53 Protein ◽  
Carcinoma Cells ◽  
Vascular Endothelial ◽  
Papillary Thyroid ◽  
Cycle Progression ◽  
Thyroid Carcinomas ◽  
Endothelial Growth Factor

Background: The clinical pathological features, as well as the cellular mechanisms of miR-195, have not been investigated in thyroid carcinoma. Objective: The aim of this study is to identify the interactions of vascular endothelial growth factor (VEGF), p53 and miR-195 in thyroid carcinoma. The clinical and pathological features of miR-195 were also investigated. Methods: The expression levels of miR-195 were identified in 123 primary thyroid carcinomas, 40 lymph nodes with metastatic papillary thyroid carcinomas and seven non-neoplastic thyroid tissues (controls) as well as two thyroid carcinoma cell lines, B-CPAP (from metastasizing human papillary thyroid carcinoma) and MB-1 (from anaplastic thyroid carcinoma), by the real-time polymerase chain reaction. Using Western blot and immunofluorescence, the effects of exogenous miR-195 on VEGF-A and p53 protein expression levels were examined. Then, cell cycle and apoptosis assays were performed to evaluate the roles of miR-195 in cell cycle progression and apoptosis. Results: The expression of miR-195 was downregulated in majority of the papillary thyroid carcinoma tissue as well as in cells. Introduction of exogenous miR-195 resulted in downregulation of VEGF-A and upregulation of p53 protein expressions. Upregulation of miR-195 in thyroid carcinoma cells resulted in cell cycle arrest. Moreover, we demonstrated that miR-195 inhibits cell cycle progression by induction of apoptosis in the thyroid carcinoma cells. Conclusion: Our findings showed for the first time that miR-195 acts as a tumour suppressor and regulates cell cycle progression and apoptosis by targeting VEGF-A and p53 in thyroid carcinoma. The current study exhibited that miR-195 might represent a potential therapeutic target for patients with thyroid carcinomas having aggressive clinical behaviour.

scholarly journals Nuclear cathepsin L activity is required for cell cycle progression of colorectal carcinoma cells

Biochimie ◽  
2016 ◽  
Vol 122 ◽  
pp. 208-218 ◽  
Author(s):  
Tripti Tamhane ◽  
Rukshala lllukkumbura ◽  
Shiying Lu ◽  
Gunhild M. Maelandsmo ◽  
Mads H. Haugen ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Colorectal Carcinoma ◽  
Cell Cycle Progression ◽  
Cathepsin L ◽  
Carcinoma Cells ◽  
Cycle Progression

scholarly journals Tubeimoside-1 induces oxidative stress-mediated apoptosis and G0/G1 phase arrest in human prostate carcinoma cells in vitro

2016 ◽  
Vol 37 (7) ◽  
pp. 950-962 ◽  
Author(s):  
Jing-bo Yang ◽  
Muhammad Khan ◽  
Yang-yang He ◽  
Min Yao ◽  
Yong-ming Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Prostate Carcinoma ◽  
Carcinoma Cells ◽  
Human Prostate ◽  
G1 Phase ◽  
Phase Arrest ◽  
G1 Phase Arrest ◽  
Human Prostate Carcinoma

scholarly journals Cubic Membranes Formation in Synchronized Human Hepatocellular Carcinoma Cells Reveals a Possible Role as a Structural Antioxidant Defense System in Cell Cycle Progression

2020 ◽  
Vol 8 ◽  
Author(s):  
Deqin Kong ◽  
Rui Liu ◽  
Jiangzheng Liu ◽  
Qingbiao Zhou ◽  
Jiaxin Zhang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Cell Cycle Progression ◽  
S Phase ◽  
Carcinoma Cells ◽  
Human Hepatocellular Carcinoma ◽  
Cycle Progression ◽  
Hepatocellular Carcinoma Cells ◽  
G2 Phase ◽  
Human Hepatocellular Carcinoma Cells

Cubic membranes (CMs) represent unique biological membrane structures with highly curved three-dimensional periodic minimal surfaces, which have been observed in a wide range of cell types and organelles under various stress conditions (e. g., starvation, virus-infection, and oxidation). However, there are few reports on the biological roles of CMs, especially their roles in cell cycle. Hence, we established a stable cell population of human hepatocellular carcinoma cells (HepG2) of 100% S phase by thymidine treatment, and determined certain parameters in G2 phase released from S phase. Then we found a close relationship between CMs formation and cell cycle, and an increase in reactive oxygen species (ROS) and mitochondrial function. After the synchronization of HepG2 cells were induced, CMs were observed through transmission electron microscope in G2 phase but not in G1, S and M phase. Moreover, the increased ATP production, mitochondrial and intracellular ROS levels were also present in G2 phase, which demonstrated a positive correlation with CMs formation by Pearson correlation analysis. This study suggests that CMs may act as an antioxidant structure in response to mitochondria-derived ROS during G2 phase and thus participate in cell cycle progression.

MAPRE1 promotes cell cycle progression of hepatocellular carcinoma cells by interacting with CDK2

2020 ◽  
Vol 44 (11) ◽  
pp. 2326-2333
Author(s):  
Xing‐hua Liang ◽  
Zheng‐ping Feng ◽  
Fo‐qiu Liu ◽  
Rong Yan ◽  
Liang‐yu Yin ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Carcinoma Cells ◽  
Cycle Progression ◽  
Hepatocellular Carcinoma Cells
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