scholarly journals Clinical-Grade Peptide-Based Inhibition of CK2 Blocks Viability and Proliferation of T-ALL Cells and Counteracts IL-7 Stimulation and Stromal Support

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1377
Author(s):  
Yasser Perera ◽  
Alice Melão ◽  
Ailyn C. Ramón ◽  
Dania Vázquez ◽  
Daniel Ribeiro ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Lymphoblastic Leukemia ◽  
Clinical Intervention ◽  
Akt Signaling ◽  
Janus Kinase ◽  
Clinical Grade ◽  
Positive Effects ◽  
Long Term Treatment ◽  
Stromal Support ◽  
The Impact

Despite remarkable advances in the treatment of T-cell acute lymphoblastic leukemia (T-ALL), relapsed cases are still a major challenge. Moreover, even successful cases often face long-term treatment-associated toxicities. Targeted therapeutics may overcome these limitations. We have previously demonstrated that casein kinase 2 (CK2)-mediated phosphatase and tensin homologue (PTEN) posttranslational inactivation, and consequent phosphatidylinositol 3-kinase (PI3K)/Akt signaling hyperactivation, leads to increased T-ALL cell survival and proliferation. We also revealed the existence of a crosstalk between CK2 activity and the signaling mediated by interleukin 7 (IL-7), a critical leukemia-supportive cytokine. Here, we evaluated the impact of CIGB-300, a the clinical-grade peptide-based CK2 inhibitor CIGB-300 on T-ALL biology. We demonstrate that CIGB-300 decreases the viability and proliferation of T-ALL cell lines and diagnostic patient samples. Moreover, CIGB-300 overcomes IL-7-mediated T-ALL cell growth and viability, while preventing the positive effects of OP9-delta-like 1 (DL1) stromal support on leukemia cells. Signaling and pull-down experiments indicate that the CK2 substrate nucleophosmin 1 (B23/NPM1) and CK2 itself are the molecular targets for CIGB-300 in T-ALL cells. However, B23/NPM1 silencing only partially recapitulates the anti-leukemia effects of the peptide, suggesting that CIGB-300-mediated direct binding to CK2, and consequent CK2 inactivation, is the mechanism by which CIGB-300 downregulates PTEN S380 phosphorylation and inhibits PI3K/Akt signaling pathway. In the context of IL-7 stimulation, CIGB-300 blocks janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway in T-ALL cells. Altogether, our results strengthen the case for anti-CK2 therapeutic intervention in T-ALL, demonstrating that CIGB-300 (given its ability to circumvent the effects of pro-leukemic microenvironmental cues) may be a valid tool for clinical intervention in this aggressive malignancy.

scholarly journals Positive Effects of PI3K/Akt Signaling Inhibition on PTEN and P53 in Prevention of Acute Lymphoblastic Leukemia Tumor Cells

2019 ◽  
Vol 9 (3) ◽  
pp. 470-480 ◽  
Author(s):  
Elahe Naderali ◽  
Behnaz Valipour ◽  
Amir Afshin Khaki ◽  
Jafar Soleymani Rad ◽  
Alireza Alihemmati ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Lymphoblastic Leukemia ◽  
Akt Signaling ◽  
Leukemia Cells ◽  
Akt Signaling Pathway ◽  
Inhibition Of Proliferation ◽  
Positive Effects ◽  
P53 Mrna

Purpose: The PI3K/Akt signaling pathway regulates cell growth, proliferation and viability in hematopoietic cells. This pathway always dysregulates in acute lymphoblastic leukemia (ALL). PTEN and P53 are tumor suppressor genes correlated with PI3K/Akt signaling pathway, and both have a tight link in regulation of cell proliferation and cell death. In this study, we investigated the effects of dual targeting of PI3K/Akt pathway by combined inhibition with nvp-BKM-120 (PI3K inhibitor) and MK-2206 (Akt inhibitor) in relation with PTEN and P53 on apoptosis and proliferation of leukemia cells. Methods: Both T and B ALL cell lines were treated with both inhibitors alone or in combination with each other, and induction of apoptosis and inhibition of proliferation were evaluated by flow cytometry. Expression levels of PTEN as well as p53 mRNA and protein were measured by real-time qRT-PCR and western blot, respectively. Results: We indicated that both inhibitors (BKM-120 and MK-2206) decreased cell viability and increased cytotoxicity in leukemia cells. Reduction in Akt phosphorylation increased PTEN and p53 mRNA and p53 protein level (in PTEN positive versus PTEN negative cell lines). Additionally, both inhibitors, particularly in combination with each other, increased apoptosis (evaluated with Annexin V and caspase 3) and reduced proliferation (Ki67 expression) in leukemia cells. However, administration of IL7 downregulated PTEN and P53 mRNA expression and rescued cancer cells following inhibition of BKM-120 and MK-2206. Conclusion: This investigation suggested that inhibition of Akt and PI3K could be helpful in leukemia treatment.

scholarly journals Macamide B Pretreatment Attenuates Neonatal Hypoxic-Ischemic Brain Damage of Mice Induced Apoptosis by Regulates Autophagy Via The PI3K/AKT Signaling Pathway

2021 ◽  
Author(s):  
Xiaoxia Yang ◽  
Mengxia Wang ◽  
Qian Zhou ◽  
Yanxian Bai ◽  
Jing Liu ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Brain Damage ◽  
Infarct Volume ◽  
Neuroprotective Effect ◽  
Akt Signaling ◽  
Akt Signaling Pathway ◽  
Ischemic Brain Damage ◽  
Ischemic Brain ◽  
Induced Apoptosis ◽  
The Impact

Abstract Lepidium meyenii (Maca) is an annual or biennial herb from South America that is a member of the genus Lepidium L. in the family Cruciferae. This herb has antioxidant, anti-apoptotic, and enhances autophagy functions and can prevent cell death, and protect neurons from ischemic damage. Macamide B, an effective active ingredient of maca, has a neuroprotective role in neonatal hypoxic-ischemic brain damage (HIBD), and the underlying mechanism of its neuroprotective effect is not yet known. The purpose of this study is to explore the impact of macamide B on HIBD-induced autophagy and apoptosis and its potential mechanism for neuroprotection. The modified Rice-Vannucci method was used to induce HIBD on 7-day-old (P7) macamide B and vehicle-pretreated pups. TTC staining was used to evaluate the cerebral infarct volume of pups, brain water content was measured to evaluate the neurological function of pups, neurobehavioral testing was used to assess functional recovery after HIBD, TUNEL and FJC staining was used to detect cell autophagy and apoptosis, and western blot analysis was used to detect the expression levels of the pro-survival signaling pathway phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) and autophagy and the apoptosis-related proteins. The results show that macamide B pretreatment can significantly decrease brain damage, improve the recovery of neural function after HIBD. At the same time, macamide B pretreatment can induce the activation of PI3K/AKT signaling pathway after HIBD, enhance autophagy, and reduce hypoxic-ischemic (HI)-induced apoptosis. In addition, 3-methyladenine (3-MA), an inhibitor of PI3K/AKT signaling pathway, significantly inhibits the increase in autophagy levels, aggravates HI-induced apoptosis, and reverses the neuroprotective effect of macamide B on HIBD. Our data indicate that macamide B pretreatment might regulate autophagy through PI3K/AKT signaling pathway, thereby reducing HIBD-induced apoptosis and exerting neuroprotective effects on neonatal HIBD. Macamide B may become a new drug for the prevention and treatment of HIBD.

Interaction between CD9 and PI3K‑p85 activates the PI3K/AKT signaling pathway in B‑lineage acute lymphoblastic leukemia

2021 ◽  
Vol 46 (1) ◽  
Author(s):  
Yi-Fen Shi ◽  
Zi-Yang Huang ◽  
Yi-Sha Huang ◽  
Ru-Jiao Dong ◽  
Chong-Yun Xing ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Signaling Pathway ◽  
Lymphoblastic Leukemia ◽  
Akt Signaling ◽  
Akt Signaling Pathway ◽  
B Lineage

scholarly journals Gene mutations in the PI3K/Akt signaling pathway were related to immune thrombocytopenia pathogenesis

2020 ◽  
Author(s):  
Ruijie Sun ◽  
Shu-Yan Liu ◽  
Xiao-Mei Zhang ◽  
Jing-Jing Zhu ◽  
Dai Yuan ◽  
...  
Keyword(s):  
Genetic Susceptibility ◽  
Signaling Pathway ◽  
Molecular Genetic ◽  
Genomic Analysis ◽  
Akt Signaling ◽  
Molecular Genetic Analysis ◽  
Missense Mutations ◽  
Functional Connections ◽  
Molecular Features ◽  
The Impact

Abstract Immune thrombocytopenic (ITP) is an autoimmune bleeding disease with genetic susceptibility. In this research, we conducted an in-depth genomic analysis of a cohort of patients and elucidate molecular features associated with disease pathogenesis of ITP. High-molecular-weight genomic DNA was extracted from freshly frozen BMBMCs (bone marrow blood mononuclear cell) in 20 active ITP patients. After this, the samples were subjected to molecular genetic analysis by whole-exome sequencing technique (WES) then, confirmed by sanger sequencing method. The enriched signaling pathway analysis and cellular processes associated with the mutated genes was performed with gene mapping to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. The results of this study showed that there were 3998 missense mutations involving 2269 genes in more than 10 individuals. Unique genetic variants including PTEN, INSR and COCH were the most associated with the pathogenesis of ITP. Functional analysis revealed these mutation genes mainly affect Phosphatidylinositol 3 kinase/serine/threonine kinase B (PI3K/Akt) signaling pathways (signal transduction) and platelet activation (immune system). Our finding further demonstrates the functional connections between these variant genes and ITP. Although the substantial mechanism and the impact of genetic variation are required further investigation, the application of next generation sequencing in ITP in this paper is a valuable method to reveal the genetic susceptibility.

scholarly journals Jak1/Stat3 Activation Alters Phosphate Metabolism Independently of Sex and Extracellular Phosphate Levels

2021 ◽  
pp. 1-9
Author(s):  
Nicole Gehring ◽  
Carla Bettoni ◽  
Carsten A. Wagner ◽  
Isabel Rubio-Aliaga
Keyword(s):  
Signaling Pathway ◽  
Mineral Metabolism ◽  
Janus Kinase ◽  
Phosphate Metabolism ◽  
Male Mice ◽  
Male And Female ◽  
Female Mice ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
The Impact

<b><i>Introduction:</i></b> Phosphate homeostasis is regulated by a complex network involving the parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), and calcitriol acting on several organs including the kidney, intestine, bone, and parathyroid gland. Previously, we showed that activation of the Janus kinase 1 (Jak1)-signal transducer and activator of transcription 3 (Stat3) signaling pathway leads to altered mineral metabolism with higher FGF23 levels, lower PTH, and higher calcitriol levels. Here, we investigated if there are sex differences in the role of Jak1/Stat3 signaling pathway on phosphate metabolism and if this pathway is sensitive to extracellular phosphate alterations. <b><i>Methods:</i></b> We used a mouse model (<i>Jak1</i><sup>S645P+/−</sup>) that resembles a constitutive activating mutation of the Jak1/Stat3 signaling pathway in humans and analyzed the impact of sex on mineral metabolism parameters. Furthermore, we challenged <i>Jak1</i><sup>S645P+/−</sup> male and female mice with a high (1.2% w/w) and low (0.1% w/w) phosphate diet and a diet with phosphate with organic origin with lower bioavailability. <b><i>Results:</i></b> Female mice, as male mice, showed higher intact FGF23 levels but no phosphaturia, and higher calcitriol and lower PTH levels in plasma. A phosphate challenge did not alter the effect of Jak1/Stat3 activation on phosphate metabolism for both genders. However, under a low phosphate diet or a diet with lower phosphate availability, the animals showed a tendency to develop hypophosphatemia. Moreover, male and female mice showed similar phosphate metabolism parameters. The only exception was higher PTH levels in male mice than those in females. <b><i>Discussion/Conclusion:</i></b> Sex and extracellular phosphate levels do not affect the impact of Jak1/Stat3 activation on phosphate metabolism.

scholarly journals CXCL12 Regulates the Cholinergic Locus and CHT1 Through Akt Signaling Pathway

2016 ◽  
Vol 40 (5) ◽  
pp. 982-992 ◽  
Author(s):  
Jing Yan ◽  
Wenhui Zhao ◽  
Meixia Guo ◽  
Xuefei Han ◽  
Zhiwei Feng
Keyword(s):  
Gene Expression ◽  
Signaling Pathway ◽  
Choline Acetyltransferase ◽  
Cholinergic Neurons ◽  
Akt Signaling ◽  
Neuronal Cultures ◽  
Mrna Levels ◽  
Akt Signaling Pathway ◽  
The Impact ◽  
And Storage

Background: CXCL12 is pivotal for cholinergic neurons, and it induces the expressions of several genes that are essential for synthesis and storage of acetylcholine(ACh), specifically choline acetyltransferase, vesicular ACh transporter (VAChT), and choline transporter. The present study explored the impact of pharmacological Akt inhibition upon cholinergic gene expression. Methods: Western blotting was employed to determine the level of p-AKT, RT-PCR to check the mRNA levels of and CHT1(choline transporter1),VAChT and ChAT, ELISA to decipher the secretion of ACh and the activity of choline acetyltransferase. Results: Here we demonstrated, in the rat pheochromocytoma cell line PC12 and in primary rat neuronal cultures, that CXCL12-evoked up-regulation of CHT1, VAChT and ChAT was mediated by Akt. Inhibition of Akt by the pharmacological inhibitor GSK690693 eliminated CXCL12-stimulated increases in cholinergic gene expression. Moreover, treatment with GSK690693 reversed CXCL12-evoked increases in choline acetyltransferase activity and ACh production. Conclusion: Our results suggest that CXCL12 contributes to cholinergic gene expression via Akt signaling pathway.

scholarly journals Butyrate Suppresses Glucose Metabolism of Colorectal Cancer Cells via GPR109a-AKT Signaling Pathway and Enhances Chemotherapy

2021 ◽  
Vol 8 ◽  
Author(s):  
Hong-Wei Geng ◽  
Feng-Yi Yin ◽  
Zhi-Fa Zhang ◽  
Xu Gong ◽  
Yun Yang
Keyword(s):  
Colorectal Cancer ◽  
Glucose Metabolism ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Histone Deacetylases ◽  
Akt Signaling ◽  
Akt Signaling Pathway ◽  
Anti Cancer ◽  
Colorectal Cancer Cells ◽  
The Impact

Glycolysis inhibitors are promising therapeutic drugs for tumor treatment, which target the uniquely elevated glucose metabolism of cancer cells. Butyrate is a critical product of beneficial microbes in the colon, which exerts extraordinary anti-cancer activities. In particular, butyrate shows biased inhibitory effects on the cell growth of cancerous colonocytes, whereas it is the major energy source for normal colonocytes. Besides its roles as the histone deacetylases (HDACs) inhibitor and the ligand for G-protein coupled receptor (GPR) 109a, the influence of butyrate on the glucose metabolism of cancerous colonocytes and the underlying molecular mechanism are not fully understood. Here, we show that butyrate markedly inhibited glucose transport and glycolysis of colorectal cancer cells, through reducing the abundance of membrane GLUT1 and cytoplasmic G6PD, which was regulated by the GPR109a-AKT signaling pathway. Moreover, butyrate significantly promoted the chemotherapeutical efficacy of 5-fluorouracil (5-FU) on cancerous colonocytes, with exacerbated impairment of DNA synthesis efficiency. Our findings provide useful information to better understand the molecular basis for the impact of butyrate on the glucose metabolism of colorectal cancer cells, which would promote the development of beneficial metabolites of gut microbiota as therapeutical or adjuvant anti-cancer drugs.

scholarly journals Effects of Rhizopus Nigricans Exopolysaccharide on Proliferation, Apoptosis, and Migration of Breast Cancer MCF-7 Cells and Akt Signaling Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-6
Author(s):  
Aizhai Xiang ◽  
Chen Ling ◽  
Wei Zhang ◽  
Honggang Chen
Keyword(s):  
Breast Cancer ◽  
Signaling Pathway ◽  
Akt Signaling ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Akt Signaling Pathway ◽  
Rhizopus Nigricans ◽  
And Migration ◽  
The Impact ◽  
Mcf 7

Objective. To study the effect of Rhizopus nigricans exopolysaccharide EPS1-1 on the proliferation, apoptosis, and migration of breast cancer MCF-7 cells. Methods. Human breast cancer MCF-7 cells were cultured in vitro and treated with different concentrations of EPS1-1. The effect of EPS1-1 on cell proliferation was tested by the CCK-8 experiment, and the effect of EPS1-1 on cell apoptosis was determined by flow cytometry. And the scratch test was used to detect the impact of EPS1-1 on cell migration. Western blot then was used to measure the expression changes of related proteins in the Akt signaling pathway. Results. Compared with the control group, treatment with EPS1-1 significantly reduced the proliferation, migration, and invasion ability of MCF-7 cells and promoted the apoptosis of MCF-7 cells in a dose-dependent manner. In terms of the underlying mechanism, EPS1-1 can significantly inhibit the phosphorylation of Akt at threonine 308 and serine 473 and cause the expression changes of downstream proliferation-related genes CCND1 and p21, apoptosis-related genes Bcl-2 and Bax, and migration-related genes Vimentin and E-cadherin in terms of their protein levels. Conclusion. EPS1-1 can inhibit the proliferation, migration, and invasion of breast cancer MCF-7 cells and promote the apoptosis of MCF-7 cells by inhibiting the activation of the Akt signaling pathway. Therefore, EPS1-1 can be used as a potential new drug or adjuvant drug for the treatment of breast cancer.

Janus Kinase/Signal Converters, and the Transcriptional Activator Signaling Pathway Promotes Lung Cancer Through Increasing M2 Macrophage

2021 ◽  
Vol 11 (4) ◽  
pp. 605-611
Author(s):  
Xinliang Zhan ◽  
Yan Wang ◽  
Jing Yang
Keyword(s):  
Lung Cancer ◽  
Bone Marrow ◽  
Signaling Pathway ◽  
Cancer Progression ◽  
Primary Lung Cancer ◽  
Janus Kinase ◽  
M2 Macrophage ◽  
Migration Ability ◽  
Stat Signaling ◽  
The Impact

Accumulating evidence highlights the salient function of JAK/STAT signaling pathway in tumorigenesis and development. But the mechanism of JAK/STAT signaling in lung cancer remains elusive. This study assessed the impact of JAK/STAT on lung tumorigenesis and its interaction with microenvironment. Mouse model of primary lung cancer was established and then treated with JAK/STAT inhibitor. Immunofluorescence was performed to analyze fluorescent labels. Transwell assay determined the cell migration ability, and Western blot, immunohistochemistry, and immunofluorescence to detect the expression of JAK/STAT key proteins. Cell proliferation was measured by Kit-8 and colony formation. JAK/STAT key proteins were upregulated in lung cancer models. Inhibition of JAK/STAT led to a decrease in proliferative, migratory and invasive capability of lung cancer cells and macrophages from bone marrow and spleen. The cell invasion ability in the bone marrow and the proliferation of macrophages in the treatment group was weakened. When co-cultured with the treated macrophages, the proliferation of LLC1 cells was inhibited. Furthermore, in vitro flow cytometry indicated that JAK/STAT affected lung cancer progression by affecting the polarization of M1/M2 macrophages. Taken altogether, JAK/STAT signal enhances M2 macrophage expression and promotes lung cancer progression.

PDGF-BB induces conversion, proliferation, migration, and collagen synthesis of oral mucosal fibroblasts through PDGFR-β/PI3K/ AKT signaling pathway

2021 ◽  
pp. 1-9
Author(s):  
Jie Wang ◽  
Jialing You ◽  
Ding Gong ◽  
Ying Xu ◽  
Bo Yang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Collagen Synthesis ◽  
Akt Signaling ◽  
Control Group ◽  
Type I ◽  
Akt Signaling Pathway ◽  
Western Blots ◽  
Tetrazolium Bromide ◽  
Thiazolyl Blue Tetrazolium Bromide ◽  
The Impact

OBJECTIVE: To explore the pathogenesis of oral submucosal fibrosis (OSF) by analyzing the impact of Platelet Derived Growth Factor (PDGF)-BB on oral mucosal fibroblasts (FB) and PDGFR-β/Phosphoinositide 3-kinase (PI3K)/serine/threonine protein kinase (AKT) signaling pathway. METHODS: The isolated and purified oral mucosal fibroblasts were divided into four groups: the control group (CON, 10% FBS DMEM), the PDGF-BB group (40 ng/ml PDGF-BB), the PDGF-BB+IMA group (40 ng/ml PDGF-BB and 60 μmol/L IMA), and the PDGF-BB+LY294002 group (40 ng/ml PDGF-BB and 48 μmol/L LY294002). Primary human FB cells were isolated and cultured for detecting the effects of PDGF-BB on α-smooth muscle actin (α-SMA) by indirect immunofluorescence. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H -tetrazolium bromide, Thiazolyl Blue Tetrazolium Bromide (MTT) method and scratch test were used to detect the proliferation and migration of FB. Western Blots were used to detect the synthesis of type I collagen (Col I) and the expression of PDGFR-β/PI3K/AKT signaling pathway-related proteins. The effects of PDGFR-β inhibitor and PI3K inhibitor were observed. RESULTS: Compared with group CON, group IMA, and group LY294002, α-SMA was upregulated in group PDGF-BB (p< 0.05), with higher OD490 nm value (p< 0.05), narrower average scratch width, and higher relative cell migration rate (p< 0.05). The expression levels of Col I, p-PDGFR-β, p-PI3K, and p-AKT were higher in group PDGF-BB (p< 0.05). CONCLUSIONS: PDGF-BB induces FB to transform into myofibroblasts (MFB) through the PDGFR-β/PI3K/AKT signaling pathway, and promotes the proliferation, migration, and collagen synthesis.

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