Interferon-γ Attenuates the Survival Activity of G-CSF through PI3K/Akt Signaling Pathway in Mouse Multipotent Progenitor Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4163-4163
Author(s):  
Hong Liu ◽  
Keichiro Mihara ◽  
Hideo Tanaka ◽  
Akiro Kimura
Keyword(s):  
Stem Cell ◽  
Progenitor Cells ◽  
Signaling Pathway ◽  
Pi3k Pathway ◽  
Akt Signaling ◽  
Dependent Manner ◽  
Akt Signaling Pathway ◽  
Hematopoietic Stem ◽  
Multipotent Progenitor Cells ◽  
Ifn Γ

Abstract Aplastic anemia (AA) is characterized by cytopenias caused by loss of stem cell and immunological relevance. We found out that impaired stem cell could be caused by excess of interferon-gamma (IFN-γ) in the serum or hypersensitivity to IFN-γ in patients with AA, notably severe AA. However, it is not clear how IFN-γ works in terms of the etiology of AA, as it exhibits diverse biological effects on cells. Thus, we investigated the essential role and the mechanism for the apoptotic function of IFN-γ against hematopoietic stem and/or progenitor cells. Although G-CSF augmented the surviving, proliferative, and differentiating activity in 32D cells, mouse multipotent progenitor cells, those effects of G-CSF were abolished by IFN-γ and they were susceptible to apoptosis with IFN-γ treatment. We focused on Akt, which was associated with the control of stem cell fate. IFN-γ did not affect the expression of Akt in 32D cells treated with G-CSF. Intriguingly, although Akt was strongly phosphorylated at Ser473 with G-CSF, IFN-γ attenuated phospho-Akt expression in dose- and time-dependent manner. As Akt is known to be phosphorylated through phosphatidylinositol-3-kinase (PI3K) pathway, we analyzed whether wortmannin, a specific inhibitor of PI3K, might have any synergistic effect on Akt phosphorylation in conjunction with IFN-γ. Wortmannin enhanced the inhibitory effect on Akt phosphorylated by G-CSF in collaboration with IFN-γ, suggesting that the activity of IFN-γ might converge on PI3K pathway. Next, to explore the downstream molecule of Akt, we examined the expression of BAD and NF-kB, which work downstream of Akt. IFN-γ increased the BAD protein reduced by G-CSF. Regardless of addition of IFN-γ, there was no alteration of NF-kB expression. IFN-γ exerted apoptosis against 32D cells through the caspase pathway. Taken together, these results suggest that IFN-γ could exert the inhibitory action on stem cells and/or progenitors by the interference of the PI3K / Akt signaling pathway in AA patients. Our findings may provide a suggestion of the treatment potential for AA such as anti-IFN-γ antibody and contribute the further understanding of AA in terms of immunological aberration.

Akt-Mediated Phosphorylation of Bmi1 Regulates Its Chromatin Association and Growth Promoting Properties.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3605-3605
Author(s):  
Yan Liu ◽  
Fan Liu ◽  
Xinyang Zhao ◽  
Goro Sashida ◽  
Anthony Deblasio ◽  
...  
Keyword(s):  
Stem Cell ◽  
Signaling Pathway ◽  
Conflicts Of Interest ◽  
Bone Marrow Failure ◽  
Akt Signaling ◽  
Polycomb Group ◽  
Akt Pathway ◽  
Akt Signaling Pathway ◽  
Self Renewal ◽  
Hematopoietic Stem

Abstract Abstract 3605 Poster Board III-541 The Polycomb group (PcG) protein Bmi1 maintains silencing of the Ink4a-Arf locus and plays a key role in stem cell self-renewal and oncogenesis. The phosphoinositide 3-kinase-Akt (PI3K-Akt) signaling pathway regulates cell survival, growth, metabolism, migration and angiogenesis. In response to acute Pten loss (which results in Akt activation), mouse embryonic fibroblasts (mefs) accumulate p16Ink4a and p19Arf and undergo senescence. Similarly, Bmi1 −/− mefs undergo premature senescence and accumulate p16Ink4a and p19Arf. PTEN and Bmi1 have similar effects on hematopoiesis; Pten deletion promotes hematopoietic stem cell (HSC) proliferation, resulting in HSC depletion, whereas loss of Bmi1 impairs HSC self-renewal capability, also leading to bone marrow failure. These similarities led us to examine whether the PI3K/Akt pathway functions upstream of Bmi1 to negatively regulate its function and indeed we found that PKB/Akt phosphorylates Bmi1 in vivo, which results in its dissociation from chromatin and in de-repression of the Ink4a-Arf locus. Furthermore, activation of the PI3K/Akt pathway suppresses the ability of Bmi1 to promote cell growth and tumourigenesis and decreases the global level of histone H2A ubiquitination. PI3K/Akt signaling is not active in hematopoietic stem cells, but it is active in more committed progenitor cells. Thus, phosphorylation and inactivation of Bmi1 by Akt may limit HSC self-renewal. Our study also provides a mechanism for the upregulation of p16Ink4a and p19Arf seen in cancer cells that have activation of the PI3K/Akt signaling pathway, and identifies important crosstalk between phosphorylation and chromatin structure. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Local delivery of USC-derived Exosome Carrying ANGPTL3 Enhance Spinal Cord Functional Recovery After Injury by Promoting Angiogenesis

2020 ◽  
Author(s):  
Xu Yan ◽  
Yong Cao ◽  
Chunyuan Chen ◽  
Hui Xie ◽  
Hongbin Lu ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Stem Cell ◽  
Signaling Pathway ◽  
Functional Recovery ◽  
Umbilical Vein ◽  
Motor Evoked Potential ◽  
Akt Signaling ◽  
Akt Signaling Pathway ◽  
Cord Injury

Abstract Background: Spinal cord injury (SCI) is a devastating clinical diseasewithout effectivetherapeuticapproach recently. In this study, we aim to investigate the effect of locally injection with exosome derived human urine stem cell (USC) embedding with hydrogelcould improve the spinal cord functional recovery after injury and the underlying mechanism.Methods:Exosome were isolate from USC andidentified by transmission electron microscopy and western blot. Functional assays using human umbilical vein endothelial cell (HUVEC) in vitro were performed to assess the effects of USC-Exosdeliverythe angiopoietin-like protein 3 (ANGPTL3) on tube formation and migration as well as their regulatory role in the PI3K/AKT signaling pathway activation. In vivo experiment we locally injection with exosome derived USC embedding with hydrogel for treatment of SCI. The effects of USC-Exos on functional recovery in spinal cord injury mice were tested by measuring motor evoked potential, histological and neovascular numbers. Meanwhile, the role of the candidate protein ANGPTL3 in USC-Exo for promoting angiogenesisin SCI was assessed.Results:In current study, we demonstrate that when given locallyinjection with exosomederivedhuman urine stem cell (USC) embeddingwith hydrogelcould pass the spinal cord blood brain barrier and delivery the angiopoietin-like protein 3 (ANGPTL3) to the injured spinal cord region. In addition, the administration of exosome derived from human USC could enhance spinal cord neurological functional recovery by promoting angiogenesis.The mechanism studies revealed that ANGPTL3 are enriched in USCexosome(USC-Exo) and required for USC exosome promoting angiogenesis. Functional studies further confirmed the effects caused by exosome derived from USC on angiogenesis wasmediated by PI3K/AKT signaling pathway. Conclusion:Collectively, our results indicated that USC derived exosome serve as a critical regulator of angiogenesis by transferring ANGPTL3 and may represent a promising novel therapeutic agent for SCI repair.

scholarly journals LncRNA MALAT1 Promotes Cancer Metastasis in Osteosarcoma via Activation of the PI3K-Akt Signaling Pathway

2018 ◽  
Vol 51 (3) ◽  
pp. 1313-1326 ◽  
Author(s):  
Yong  Chen ◽  
Wending Huang ◽  
Wei Sun ◽  
Biqiang Zheng ◽  
Chunmeng Wang ◽  
...  
Keyword(s):  
Stem Cell ◽  
Tumor Growth ◽  
Signaling Pathway ◽  
Cancer Metastasis ◽  
Soft Tissues ◽  
Akt Signaling ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Osteosarcoma Cell ◽  
Akt Signaling Pathway

Background/Aims: LncRNAs have been reported to be vital regulators of the progression of osteosarcoma, although the underlying mechanisms are not completely understood. Methods: The levels of MALAT1 and miR-129-5p expression were measured using qRT-PCR. Cell growth was determined using the CCK-8 and colony formation assays. Cell migration and invasion were detected using the wound healing and Transwell invasion assays, respectively. Tumor growth was determined with a xenograft model. Results: MALAT1 was significantly up-regulated in osteosarcoma tissues compared with adjacent non-tumor soft tissues. Overexpression of MALAT1 promoted osteosarcoma cell proliferation, migration, and invasion in vitro and enhanced tumor growth in a tumor xenograft mouse model. MALAT1 promoted osteosarcoma progression by modulating stem cell-like properties. Moreover, rescue experiment and luciferase reporter assay results indicated that MALAT1 modulates RET expression by sponging miR-129-5p in osteosarcomas. Furthermore, MALAT1 augmented the expression of downstream proteins of the RET-Akt pathway. MALAT1 was consistently significantly increased in osteosarcoma tissues and MALAT1 expression was positively correlated with tumor size and metastasis. High expression of MALAT1 was significantly associated with poor outcomes in patients with osteosarcomas. MALAT1 expression was positively related to RET and negatively related to miR-129-5p in osteosarcoma samples and xenograft tumors. MALAT1 functioned as an oncogenic lncRNA in osteosarcomas and was as an independent prognostic indicator. Conclusion: Our data revealed for the first time that MALAT1 increases stem cell-like properties by up-regulating RET via sponging miR-129-5p, and thus activates the PI3K-Akt signaling pathway and provides potential therapeutic targets for osteosarcoma treatment.

scholarly journals Staurosporine suppresses survival of HepG2 cancer cells through Omi/HtrA2-mediated inhibition of PI3K/Akt signaling pathway

Tumor Biology ◽  
2017 ◽  
Vol 39 (3) ◽  
pp. 101042831769431 ◽  
Author(s):  
Youming Ding ◽  
Bin Wang ◽  
Xiaoyan Chen ◽  
Yu Zhou ◽  
Jianhui Ge
Keyword(s):  
Cell Death ◽  
Cell Viability ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Human Cancer ◽  
Akt Signaling ◽  
Therapeutic Effects ◽  
Concomitant Treatment ◽  
Dependent Manner ◽  
Akt Signaling Pathway

Staurosporine, which is an inhibitor of a broad spectrum of protein kinases, has shown cytotoxicity on several human cancer cells. However, the underlying mechanism is not well understood. In this study, we examined whether and how this compound has an inhibitory action on phosphatidylinositol 3-kinase (PI3K)/Akt pathway in vitro using HepG2 human hepatocellular carcinoma cell line. Cell viability and apoptosis were determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and terminal deoxyribonucleotidyl transferase–mediated dUTP-digoxigenin nick end labeling (TUNEL) assay, respectively. Glutathione S-transferase (GST) pull-down assay and co-immunoprecipitation were performed to detect protein–protein interactions. Small interfering RNA (siRNA) was used to silence the expression of targeted protein. We found that staurosporine significantly decreased cell viability and increased cell apoptosis in a concentration- and time-dependent manner in HepG2 cancer cells, along with the decreased expressions of PDK1 protein and Akt phosphorylation. Staurosporine was also found to enhance Omi/HtrA2 release from mitochondria. Furthermore, Omi/HtrA2 directly bound to PDK1. Pharmacological and genetic inhibition of Omi/HtrA2 restored protein levels of PDK1 and protected HepG2 cancer cells from staurosporine-induced cell death. In addition, staurosporine was found to activate autophagy. However, inhibition of autophagy exacerbated cell death under concomitant treatment with staurosporine. Taken together, our results indicate that staurosporine induced cytotoxicity response by inhibiting PI3K/Akt signaling pathway through Omi/HtrA2-mediated PDK1 degradation, and the process provides a novel mechanism by which staurosporine produces its therapeutic effects.

scholarly journals Androgen Plays a Carcinogenic Role in EOC via the PI3K/AKT Signaling Pathway in an AR-Dependent Manner

2021 ◽  
Vol 12 (6) ◽  
pp. 1815-1825
Author(s):  
Yanfang Li ◽  
Sha Li ◽  
Yizhou Zhang ◽  
Shuhong Shi ◽  
Shan Qin ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Akt Signaling ◽  
Dependent Manner ◽  
Akt Signaling Pathway

scholarly journals Parthenolide Augments the Chemosensitivity of Non-small-Cell Lung Cancer to Cisplatin via the PI3K/AKT Signaling Pathway

2021 ◽  
Vol 8 ◽  
Author(s):  
Li-Mei Wu ◽  
Xiao-Zhong Liao ◽  
Yan Zhang ◽  
Zi-Rui He ◽  
Shi-Qing Nie ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Signaling Pathway ◽  
Cell Lung Cancer ◽  
Caspase 3 ◽  
Akt Signaling ◽  
Small Cell ◽  
Dependent Manner ◽  
Akt Signaling Pathway ◽  
Small Cell Lung

The mortality rate of non-small-cell lung cancer (NSCLC) remains high worldwide. Although cisplatin-based chemotherapy may greatly enhance patient prognosis, chemotherapy resistance remains an obstacle to curing patients with NSCLC. Therefore, overcoming drug resistance is the main route to successful treatment, and combinatorial strategies may have considerable clinical value in this effort. In this study, we observed that both parthenolide (PTL) and cisplatin (DDP) inhibited the growth of NSCLC cells in a dose- and time-dependent manner. The combination of PTL and DDP presented a synergistic inhibitory effect on NSCLC at a ratio of 50:1. The combination of PTL and DDP synergistically inhibited cell migration and invasion, inhibited cell cycle progression, and induced apoptosis of A549 and PC9 cells. Bioinformatics and network pharmacology analysis indicated that PTL may primarily affect the phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway. After treatment with PTL and DDP either alone or in combination, Western blot analysis revealed that the proteins levels of Bax and cleaved Caspase-3 were upregulated, while p-PI3K, p-Akt, Caspase-3, and Bcl-2 proteins were downregulated. Among these alterations, the combination of PTL and DDP was found to exhibit the most significant effects. PTL might therefore be considered as a new option for combination therapy of NSCLC.

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