scholarly journals M2 Receptor Activation Counteracts the Glioblastoma Cancer Stem Cell Response to Hypoxia Condition

2020 ◽  
Vol 21 (5) ◽  
pp. 1700 ◽  
Author(s):  
Ilaria Cristofaro ◽  
Chiara Limongi ◽  
Paola Piscopo ◽  
Alessio Crestini ◽  
Claudia Guerriero ◽  
...  
Keyword(s):  
Cell Cycle Progression ◽  
Hypoxic Condition ◽  
Receptor Activation ◽  
Pcr Analysis ◽  
Hypoxia Inducible Factors ◽  
Cycle Progression ◽  
Hypoxic Conditions ◽  
Inhibit Cell Cycle Progression ◽  
Tumor Types ◽  
M2 Muscarinic Receptors

Glioblastoma multiforme (GBM) is the most malignant brain tumor. Hypoxic condition is a predominant feature of the GBM contributing to tumor growth and resistance to conventional therapies. Hence, the identification of drugs able to impair GBM malignancy and aggressiveness is considered of great clinical relevance. Previously, we demonstrated that the activation of M2 muscarinic receptors, through the agonist arecaidine propargyl ester (Ape), arrests cell proliferation in GBM cancer stem cells (GSCs). In the present work, we have characterized the response of GSCs to hypoxic condition showing an upregulation of hypoxia-inducible factors and factors involved in the regulation of GSCs survival and proliferation. Ape treatment in hypoxic conditions is however able to inhibit cell cycle progression, causing a significant increase of aberrant mitosis with consequent decreased cell survival. Additionally, qRT-PCR analysis suggest that Ape downregulates the expression of stemness markers and miR-210 levels, one of the main regulators of the responses to hypoxic condition in different tumor types. Our data demonstrate that Ape impairs the GSCs proliferation and survival also in hypoxic condition, negatively modulating the adaptive response of GSCs to hypoxia.

scholarly journals Hyperbaric oxygen promotes not only glioblastoma proliferation but also chemosensitization by inhibiting HIF1α/HIF2α-Sox2

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Pan Wang ◽  
Sheng Gong ◽  
Jinyu Pan ◽  
Junwei Wang ◽  
Dewei Zou ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Cycle Arrest ◽  
Hyperbaric Oxygen ◽  
Cell Cycle Progression ◽  
Malignant Progression ◽  
Cycle Progression ◽  
Chemotherapy Sensitivity ◽  
Hypoxic Conditions ◽  
Cycle Arrest

AbstractThere exists a consensus that combining hyperbaric oxygen (HBO) and chemotherapy promotes chemotherapy sensitivity in GBM cells. However, few studies have explored the mechanism involved. HIF1α and HIF2α are the two main molecules that contribute to GBM malignant progression by inhibiting apoptosis or maintaining stemness under hypoxic conditions. Moreover, Sox2, a marker of stemness, also contributes to GBM malignant progression through stemness maintenance or cell cycle arrest. Briefly, HIF1α, HIF2α and Sox2 are highly expressed under hypoxia and contribute to GBM growth and chemoresistance. However, after exposure to HBO for GBM, whether the expression of the above factors is decreased, resulting in chemosensitization, remains unknown. Therefore, we performed a series of studies and determined that the expression of HIF1α, HIF2α and Sox2 was decreased after HBO and that HBO promoted GBM cell proliferation through cell cycle progression, albeit with a decrease in stemness, thus contributing to chemosensitization via the inhibition of HIF1α/HIF2α-Sox2.

Abstract 1: Hypoxia-Induced Decrease In Cardiac Stem Cell Proliferation Is Associated With Downregulation Of Sirtuin 1

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Michael Bellio ◽  
Claudia O Rodrigues ◽  
Victoria Florea ◽  
Wayne Balkan ◽  
Joshua M Hare ◽  
...  
Keyword(s):  
Cell Cycle Progression ◽  
Scar Tissue ◽  
Sirtuin 1 ◽  
Myocardial Tissue ◽  
Cardiac Stem Cells ◽  
Regenerative Capacity ◽  
Cycle Progression ◽  
Ischemic Hypoxia ◽  
Hypoxic Conditions ◽  
Complete Regeneration

Background: Myocardial infarction (MI) produces severe hypoxia within regions of the myocardium, resulting in the formation of scar tissue and significant cardiac cell death. Adult hearts contain endogenous cardiac stem cells (CSCs) that have regenerative capacity and participate in myocardial tissue homeostasis and repair post-MI, but are insufficient to promote complete regeneration. The histone deacetylase Sirtuin 1 (SIRT1) likely mediates this hypoxia-induced decrease in regeneration via roles in cell cycle progression and conferring protection from senescence and oxidative damage. Hypothesis: Hypoxia decreases CSC proliferation through reduced SIRT1-mediated deacetylation. Methods and Results: Murine CSCs were grown at room air (21% O2), physiologic (5% O2), and ischemic hypoxic (0.5% O2) conditions for 72 hours. Ischemic hypoxia, but not physiologic, reduced CSC proliferation and DNA synthesis to 25±2.0% (N=3; p<0.05) and 54±7.0% (N=7; p<0.05), respectively, relative to cells grown in room air. SIRT1 protein expression was decreased by 58±10.0% (N=4; p<0.05) and acetylation of Histone H3 Lys9 (2.4-fold; N=5; p<0.05) and p53 Lys379 (1.64-fold; N=4; p<0.05) were increased after 72 hours of growth in 0.5% compared to 21% O2. However, SIRT1 mRNA transcripts remained unchanged. Furthermore, SIRT1 protein was 59±6.0% less stable (N=4; p<0.05) following 8 hours of cyclohexamide treatment in CSCs exposed to 0.5% O2 for 72 hours compared to CSCs exposed to 21% O2. SIRT1 knockdown by RNA interference significantly reduced proliferation of CSCs grown in room air (N=3 and, p<0.05), similar to that observed in un-transfected cells grown under ischemic hypoxia conditions. Conclusion: The decrease in CSC proliferation with hypoxia is in part due to a reduction in SIRT1 protein stability. These results suggest that SIRT1 expression is regulated post-translationally and support a role for SIRT1 in preserving CSC self-renewal under hypoxic conditions.

scholarly journals Cyclin G2, a novel target of sulindac to inhibit cell cycle progression in colorectal cancer

2020 ◽  
Author(s):  
Hongyou Zhao ◽  
Bin Yi ◽  
Zhipin Liang ◽  
Ches’Nique Phillips ◽  
Hui-Yi Lin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Inhibit Cell Cycle Progression ◽  
Cyclin G2 ◽  
Novel Target

scholarly journals MicroRNAs in the miR-106b Family Regulate p21/CDKN1A and Promote Cell Cycle Progression

2008 ◽  
Vol 28 (7) ◽  
pp. 2167-2174 ◽  
Author(s):  
Irena Ivanovska ◽  
Alexey S. Ball ◽  
Robert L. Diaz ◽  
Jill F. Magnus ◽  
Miho Kibukawa ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Kinase Inhibitor ◽  
Phenotype Microarray ◽  
Loss Of Function ◽  
Cycle Progression ◽  
Multiple Tumor ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Expression Of Genes ◽  
Tumor Types

ABSTRACT microRNAs in the miR-106b family are overexpressed in multiple tumor types and are correlated with the expression of genes that regulate the cell cycle. Consistent with these observations, miR-106b family gain of function promotes cell cycle progression, whereas loss of function reverses this phenotype. Microarray profiling uncovers multiple targets of the family, including the cyclin-dependent kinase inhibitor p21/CDKN1A. We show that p21 is a direct target of miR-106b and that its silencing plays a key role in miR-106b-induced cell cycle phenotypes. We also show that miR-106b overrides a doxorubicin-induced DNA damage checkpoint. Thus, miR-106b family members contribute to tumor cell proliferation in part by regulating cell cycle progression and by modulating checkpoint functions.

Newly identified structurally disparate modulators of osmosensitive taurine efflux inhibit cell cycle progression

2003 ◽  
Vol 474 (2-3) ◽  
pp. 185-193 ◽  
Author(s):  
Mark J. Belsey ◽  
Steven J. Culliford ◽  
Richard M. Morley ◽  
Harry J. Witchel ◽  
Roland Z. Kozlowski
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Inhibit Cell Cycle Progression ◽  
Taurine Efflux

scholarly journals Cell cycle progression and transmitotic apoptosis resistance promote escape from extrinsic apoptosis

2021 ◽  
Author(s):  
Nadine Pollak ◽  
Aline Lindner ◽  
Dirke Imig ◽  
Karsten Kuritz ◽  
Jacques S. Fritze ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Receptor Activation ◽  
S Phase ◽  
Apoptosis Resistance ◽  
Cycle Progression ◽  
Extrinsic Apoptosis ◽  
Primed State ◽  
Pass Through ◽  
Cycle Dependent

Extrinsic apoptosis relies on TNF-family receptor activation by immune cells or receptor-activating biologics. Here, we monitored cell cycle progression at minutes resolution to relate apoptosis kinetics and cell-to-cell heterogeneities in death decisions to cell cycle phases. Interestingly, we found that cells in S phase delay TRAIL receptor-induced death in favour for mitosis, thereby passing on an apoptosis-primed state to their offspring. This translates into two distinct fates, apoptosis execution post mitosis or cell survival from inefficient apoptosis. Transmitotic resistance is linked to Mcl-1 upregulation and increased accumulation at mitochondria from mid S phase onwards, which allows cells to pass through mitosis with activated caspase-8, and with cells escaping apoptosis after mitosis sustaining sublethal DNA damage. Antagonizing Mcl-1 suppresses cell cycle-dependent delays in apoptosis, prevents apoptosis-resistant progression through mitosis and averts unwanted survival from apoptosis induction. Cell cycle progression therefore modulates signal transduction during extrinsic apoptosis, with Mcl-1 governing decision making between death, proliferation and survival. Cell cycle progression thus is a crucial process from which cell-to-cell heterogeneities in fates and treatment outcomes emerge in isogenic cell populations during extrinsic apoptosis.

scholarly journals M2 receptor activation inhibits cell cycle progression and survival in human glioblastoma cells

2013 ◽  
Vol 17 (4) ◽  
pp. 552-566 ◽  
Author(s):  
Michela Ferretti ◽  
Cinzia Fabbiano ◽  
Maria Di Bari ◽  
Claudia Conte ◽  
Emilia Castigli ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Receptor Activation ◽  
Glioblastoma Cells ◽  
Cycle Progression ◽  
Human Glioblastoma ◽  
Human Glioblastoma Cells

scholarly journals P2Y2 purinergic receptor activation is essential for efficient hepatocyte proliferation in response to partial hepatectomy

2014 ◽  
Vol 307 (11) ◽  
pp. G1073-G1087 ◽  
Author(s):  
Bryan C. Tackett ◽  
Hongdan Sun ◽  
Yu Mei ◽  
Janielle P. Maynard ◽  
Sayuri Cheruvu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Partial Hepatectomy ◽  
Cell Cycle Progression ◽  
Purinergic Receptors ◽  
Purinergic Receptor ◽  
Receptor Activation ◽  
Hepatocyte Proliferation ◽  
Receptor Subtypes ◽  
Cycle Progression ◽  
The Impact

Extracellular nucleotides via activation of P2 purinergic receptors influence hepatocyte proliferation and liver regeneration in response to 70% partial hepatectomy (PH). Adult hepatocytes express multiple P2Y (G protein-coupled) and P2X (ligand-gated ion channels) purinergic receptor subtypes. However, the identity of key receptor subtype(s) important for efficient hepatocyte proliferation in regenerating livers remains unknown. To evaluate the impact of P2Y2 purinergic receptor-mediated signaling on hepatocyte proliferation in regenerating livers, wild-type (WT) and P2Y2 purinergic receptor knockout (P2Y2−/−) mice were subjected to 70% PH. Liver tissues were analyzed for activation of early events critical for hepatocyte priming and subsequent cell cycle progression. Our findings suggest that early activation of p42/44 ERK MAPK (5 min), early growth response-1 (Egr-1) and activator protein-1 (AP-1) DNA-binding activity (30 min), and subsequent hepatocyte proliferation (24–72 h) in response to 70% PH were impaired in P2Y2−/− mice. Interestingly, early induction of cytokines (TNF-α, IL-6) and cytokine-mediated signaling (NF-κB, STAT-3) were intact in P2Y2−/− remnant livers, uncovering the importance of cytokine-independent and nucleotide-dependent early priming events critical for subsequent hepatocyte proliferation in regenerating livers. Hepatocytes isolated from the WT and P2Y2−/− mice were treated with ATP or ATPγS for 5–120 min and 12–24 h. Extracellular ATP alone, via activation of P2Y2 purinergic receptors, was sufficient to induce ERK phosphorylation, Egr-1 protein expression, and key cyclins and cell cycle progression of hepatocytes in vitro. Collectively, these findings highlight the functional significance of P2Y2 purinergic receptor activation for efficient hepatocyte priming and proliferation in response to PH.

Sign in / Sign up

Export Citation Format

Share Document