scholarly journals Genetic inactivation of Cdk7 leads to cell cycle arrest and induces premature aging due to adult stem cell exhaustion

2012 ◽  
Vol 31 (11) ◽  
pp. 2498-2510 ◽  
Author(s):  
Miguel Ganuza ◽  
Cristina Sáiz-Ladera ◽  
Marta Cañamero ◽  
Gonzalo Gómez ◽  
Ralph Schneider ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cell ◽  
Cell Cycle Arrest ◽  
Adult Stem Cell ◽  
Premature Aging ◽  
Cell Exhaustion ◽  
Genetic Inactivation ◽  
Cycle Arrest

scholarly journals Glioblastoma Multiforme Stem Cell Cycle Arrest by Alkylaminophenol through the Modulation of EGFR and CSC Signaling Pathways

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 681 ◽  
Author(s):  
Phuong Doan ◽  
Aliyu Musa ◽  
Akshaya Murugesan ◽  
Vili Sipilä ◽  
Nuno R. Candeias ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cell ◽  
Glioblastoma Multiforme ◽  
Cell Cycle Arrest ◽  
Signaling Pathways ◽  
Cell Lines ◽  
Cell Population ◽  
Significant Role ◽  
Dependent Manner ◽  
Cycle Arrest

Cancer stem cells (CSCs), a small subpopulation of cells existing in the tumor microenvironment promoting cell proliferation and growth. Targeting the stemness of the CSC population would offer a vital therapeutic opportunity. 3,4-Dihydroquinolin-1(2H)-yl)(p-tolyl)methyl)phenol (THTMP), a small synthetic phenol compound, is proposed to play a significant role in controlling the CSC proliferation and survival. We assessed the potential therapeutic effects of THTMP on glioblastoma multiforme (GBM) and its underlying mechanism in various signaling pathways. To fully comprehend the effect of THTMP on the CSCs, CD133+ GBM stem cell (GSC) and CD133- GBM Non-stem cancer cells (NSCC) population from LN229 and SNB19 cell lines was used. Cell cycle arrest, apoptosis assay and transcriptome analysis were performed for individual cell population. THTMP strongly inhibited NSCC and in a subtle way for GSC in a time-dependent manner and inhibit the resistance variants better than that of temozolomide (TMZ). THTMP arrest the CSC cell population at both G1/S and G2/M phase and induce ROS-mediated apoptosis. Gene expression profiling characterize THTMP as an inhibitor of the p53 signaling pathway causing DNA damage and cell cycle arrest in CSC population. We show that the THTMP majorly affects the EGFR and CSC signaling pathways. Specifically, modulation of key genes involved in Wnt, Notch and Hedgehog, revealed the significant role of THTMP in disrupting the CSCs’ stemness and functions. Moreover, THTMP inhibited cell growth, proliferation and metastasis of multiple mesenchymal patient-tissue derived GBM-cell lines. THTMP arrests GBM stem cell cycle through the modulation of EGFR and CSC signaling pathways.

scholarly journals Loss of p53-mediated cell-cycle arrest, senescence and apoptosis promotes genomic instability and premature aging

Oncotarget ◽  
2016 ◽  
Vol 7 (11) ◽  
pp. 11838-11849 ◽  
Author(s):  
Tongyuan Li ◽  
Xiangyu Liu ◽  
Le Jiang ◽  
James Manfredi ◽  
Shan Zha ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Genomic Instability ◽  
Premature Aging ◽  
Cycle Arrest

scholarly journals The Histone Code of Senescence

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 466 ◽  
Author(s):  
Harikrishnareddy Paluvai ◽  
Eros Di Giorgio ◽  
Claudio Brancolini
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Arrest ◽  
Cellular Response ◽  
Premature Aging ◽  
Physiological Processes ◽  
Cycle Arrest ◽  
Damage Response ◽  
Permanent Cell ◽  
Second Wave

Senescence is the end point of a complex cellular response that proceeds through a set of highly regulated steps. Initially, the permanent cell-cycle arrest that characterizes senescence is a pro-survival response to irreparable DNA damage. The maintenance of this prolonged condition requires the adaptation of the cells to an unfavorable, demanding and stressful microenvironment. This adaptation is orchestrated through a deep epigenetic resetting. A first wave of epigenetic changes builds a dam on irreparable DNA damage and sustains the pro-survival response and the cell-cycle arrest. Later on, a second wave of epigenetic modifications allows the genomic reorganization to sustain the transcription of pro-inflammatory genes. The balanced epigenetic dynamism of senescent cells influences physiological processes, such as differentiation, embryogenesis and aging, while its alteration leads to cancer, neurodegeneration and premature aging. Here we provide an overview of the most relevant histone modifications, which characterize senescence, aging and the activation of a prolonged DNA damage response.

Mesenchymal stem cell-derived exosomes suppress proliferation of T cells by inducing cell cycle arrest through p27kip1/Cdk2 signaling

2020 ◽  
Vol 225 ◽  
pp. 16-22 ◽  
Author(s):  
Sunho Lee ◽  
Sueon Kim ◽  
Hyunwoo Chung ◽  
Ji Hwan Moon ◽  
Seong Jun Kang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Cell Cycle Arrest ◽  
Cycle Arrest

scholarly journals Genetic Inactivation of the Transcription Factor TIF-IA Leads to Nucleolar Disruption, Cell Cycle Arrest, and p53-Mediated Apoptosis

2005 ◽  
Vol 19 (1) ◽  
pp. 77-87 ◽  
Author(s):  
Xuejun Yuan ◽  
Yonggang Zhou ◽  
Emilio Casanova ◽  
Minqiang Chai ◽  
Eva Kiss ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transcription Factor ◽  
Cell Cycle Arrest ◽  
Genetic Inactivation ◽  
Cycle Arrest

scholarly journals Human Wharton’s Jelly Stem Cell Secretions Inhibit Human Leukemic Cell Line K562 in vitro by Inducing Cell Cycle Arrest and Apoptosis

2021 ◽  
Vol 9 ◽  
Author(s):  
Muneerah A. H. Huwaikem ◽  
Gauthaman Kalamegam ◽  
Ghadeer Alrefaei ◽  
Farid Ahmed ◽  
Roaa Kadam ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cell ◽  
Cell Cycle Arrest ◽  
Cell Line ◽  
Inflammatory Cytokine ◽  
K562 Cells ◽  
Cycle Arrest ◽  
Tnf Α ◽  
Ifn Γ

Emerging resistance to the tyrosine kinase inhibitors that target the BCR-ABL1 oncoprotein has prompted research for novel therapeutics against chronic myeloid leukemia (CML). Herein, we evaluated the tumor inhibitory properties of the human Wharton’s jelly stem cells (hWJSCs) co-culture (hWJSC-CC) and their extracts, namely, the hWJSC-conditioned medium (hWJSC-CM; 100%) and hWJSC-lysate (hWJSC-L; 15 μg/ml), on a CML cell line K562 in vitro. The hWJSCs expressed mesenchymal stem cell (MSC)-related cluster of differentiation (CD) markers and demonstrated mesodermal tissue differentiation potential. The cell metabolic activity showed a mean maximal decrease in the K562 cells by 49.12, 41.98, and 68.80% following treatment with the hWJSC-CC, hWJSC-CM, and hWJSC-L, respectively, at 72 h. The sub-G1 population in the cell cycle was decreased by 3.2, 4.5, and 3.8% following treatment with the hWJSC-CC, hWJSC-CM, and hWJSC-L, whereas the G2/M cell population was increased by 13.7 and 12.5% with the hWJSC-CM and hWJSC-L, respectively, at 48 h. Annexin V–allophycocyanin (APC) assay showed an increase in the apoptotic cells by 4.0, 3.9, and 4.5% at 48 h. The expression of pro-apoptotic BAX and CASP3 genes were increased, whereas BIRC5 (Survivin) was decreased compared with the control. The pro-inflammation-related genes, namely, IFN-γ, TNF-α, IL-1β, IL-6, IL-8, and IL-12A, were decreased, whereas the anti-inflammatory genes, namely, IL-4 and IL-10, were increased following treatment with the hWJSC-CC, hWJSC-CM, and hWJSC-L at 48 h. Multiplex bead-based cytokine assay also demonstrated decreases in the pro-inflammatory cytokines (IFN-γ, TNF-α, IL-1β, IL-6, and IL-12) and an increase in the anti-inflammatory cytokine (IL-10) compared with the control. The pro-inflammatory cytokine IL-8 showed an increase with the hWJSC-CC and decreases with both the hWJSC-CM and the hWJSC-L. The hWJSCs and their extracts inhibited the K562 cells by causing cell cycle arrest and inducing apoptosis via the soluble cellular factors. However, an in vivo evaluation is necessary to unravel the true potential of the hWJSCs and their extracts before its use in CML inhibition.

scholarly journals Dietary compound proanthocyanidins from Chinese bayberry (Myrica rubraSieb. et Zucc.) leaves attenuate chemotherapy-resistant ovarian cancer stem cell traitsviatargeting the Wnt/β-catenin signaling pathway and inducing G1 cell cycle arrest

2018 ◽  
Vol 9 (1) ◽  
pp. 525-533 ◽  
Author(s):  
Yu Zhang ◽  
Shiguo Chen ◽  
Chaoyang Wei ◽  
Gary O. Rankin ◽  
Xingqian Ye ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Ovarian Cancer ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Chinese Bayberry ◽  
Cycle Arrest ◽  
G1 Cell Cycle Arrest

Chinese bayberry leaves are found to aid treatment of chemotherapy-resistant cancer cells.

Foxo Transcription Factor Activity Is Retained in Quiescent Chronic Myeloid Leukaemia Stem Cells and Activated by Tyrosine Kinase Inhibitors to Mediate “induced-quiescence” in More Mature progenitors.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 187-187 ◽  
Author(s):  
Daniela Cilloni ◽  
Francesca Pellicano ◽  
Vignir G Helgason ◽  
Cristina Panuzzo ◽  
Francesca Messa ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Stem Cell ◽  
Tyrosine Kinase ◽  
Cell Cycle Arrest ◽  
Progenitor Cells ◽  
Transcriptional Activity ◽  
Kinase Inhibitors ◽  
Akt Pathway ◽  
Cycle Arrest

Abstract Abstract 187 First line therapy for CML involves tyrosine kinase inhibitors (TKIs) which can induce rapid cytogenetic responses in the majority of patients in chronic phase (CP), but do not eliminate BCR-ABL transcripts in the majority, suggesting persistence of residual disease. These findings, together with the rapid kinetics of relapse in patients who discontinue TKIs, suggest the presence of a reservoir of TKI-resistant leukaemic stem cells, although the mechanism for TKI-insensitivity of CML stem cells remains unclear. The FoxO family of transcription factors is mainly regulated by PI3K/Akt induced phosphorylation, resulting in nuclear exclusion and degradation. FOXO activity is implicated in maintaining haemopoietic stem cell (HSC) quiescence. Its transcriptional activity in normal HSC results in cell cycle arrest by expression of p27, p130, p21, down-regulation of Cyclin D and protection from oxidative stress. Cell line studies suggest that FOXOs may play a central role in the anti-proliferative effects of TKIs, but their role in primary CML stem cells has not been previously investigated. Methods: Quiescent CML stem cells were isolated phenotypically (Lin−CD34+38−) by FACS from the total CD34+ stem/progenitor cell population and D-FISH analysis performed to determine the percentage of Ph+ cells. The expression levels of Spred1, FOXO1, FOXO3a, FOXO4 and Cyclin D1 were evaluated by Real-Time-PCR. Protein levels and localization were studied by Western blot, immunofluorescence and FACS. EMSA assay was used to evaluate FOXO3a DNA binding activity. K562 cells were transfected with wt FOXO3a and the constitutively active triple mutant (TM) form of FOXO. After transfection, proliferation and apoptosis were tested using incorporation of H3 thymidine and annexin V detection by FACS, respectively. Results: We found that BCR-ABL, through activation of the PI3K/Akt pathway, induces phosphorylation and cytoplasmic localization of FOXO in CD34+ CML cells, thereby blocking its transcriptional activity as demonstrated by EMSA and by the inhibition of FOXO target genes, including Spred1. Incubation with TKIs decreased phosphorylation and induced re-localization of FOXO to the nucleus in CD34+ CML cells, thus restoring FOXO transcriptional activity. This resulted in decreased levels of Cyclin D1 and reduced ROS. Similar effects and a dramatic reduction of cell proliferation, accompanied by significant apoptosis, were observed by forcing the expression of FOXO3a in K562 through transfection of the TM form, confirming the role of FOXO in inducing cell cycle arrest. Incubation experiments using LY294002, rapamycin and TKIs established that the reactivation of FOXO by TKI is mediated by the PI3K/Akt pathway. Interestingly, we found that phosphorylation of FOXO1, 3a and 4 was higher (i.e. cytoplasmic and inactive) in proliferating CD34+38+ CML cells, as compared to more primitive and quiescent CD34+38−90+ CML cells, although the activity of BCR-ABL, measured by analysis of p-CrKL was found to be similar in both populations, indicating that although present, BCR-ABL was not inducing phosphorylation of FOXO in the quiescent population. In this sense the quiescent CML stem cells resembled normal HSC in terms of FOXO regulation. In conclusion our data indicate that TKIs initiate a process in CML stem and progenitor cells that maintains their quiescence and therefore potential resistance to TKIs themselves. The anti-proliferative activity of TKIs against primary CML CD34+ cells is mediated, at least in part, by the re-activation of FOXO1, 3a and 4. BCR-ABL appears to play a different role in more mature progenitor cells compared to primitive quiescent stem cells, suggesting the possibility of an incomplete activity of BCR-ABL at the stem cell level or alternatively, the possibility that FOXO activity at this level provides the dominant signal responsible for intrinsic quiescence. Disclosures: No relevant conflicts of interest to declare.

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