scholarly journals Nuclear upregulation of class I phosphoinositide 3-kinase p110β correlates with high 47S rRNA levels in cancer cells

2021 ◽  
Vol 134 (3) ◽  
pp. jcs246090 ◽  
Author(s):  
Fatemeh Mazloumi Gavgani ◽  
Thomas Karlsson ◽  
Ingvild L. Tangen ◽  
Andrea Papdiné Morovicz ◽  
Victoria Smith Arnesen ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Molecular Mechanisms ◽  
Mrna Level ◽  
Class I ◽  
High Grade ◽  
Catalytic Subunits ◽  
Protein Levels ◽  
Nuclear Compartments ◽  
Ec Cells ◽  
Phosphoinositide 3 Kinase

ABSTRACTThe class I phosphoinositide 3-kinase (PI3K) catalytic subunits p110α and p110β are ubiquitously expressed but differently targeted in tumours. In cancer, PIK3CB (encoding p110β) is seldom mutated compared with PIK3CA (encoding p110α) but can contribute to tumorigenesis in certain PTEN-deficient tumours. The underlying molecular mechanisms are, however, unclear. We have previously reported that p110β is highly expressed in endometrial cancer (EC) cell lines and at the mRNA level in primary patient tumours. Here, we show that p110β protein levels are high in both the cytoplasmic and nuclear compartments in EC cells. Moreover, high nuclear:cytoplasmic staining ratios were detected in high-grade primary tumours. High levels of phosphatidylinositol (3,4,5)-trisphosphate [PtdIns(3,4,5)P3] were measured in the nucleus of EC cells, and pharmacological and genetic approaches showed that its production was partly dependent upon p110β activity. Using immunofluorescence staining, p110β and PtdIns(3,4,5)P3 were localised in the nucleolus, which correlated with high levels of 47S pre-rRNA. p110β inhibition led to a decrease in both 47S rRNA levels and cell proliferation. In conclusion, these results present a nucleolar role for p110β that may contribute to tumorigenesis in EC.This article has an associated First Person interview with Fatemeh Mazloumi Gavgani, joint first author of the paper.

FOXD3 inhibits cell proliferation, migration, and invasion in nasopharyngeal carcinoma through regulation of the PI3K–Akt pathway

2020 ◽  
Vol 98 (6) ◽  
pp. 653-660 ◽  
Author(s):  
Xiaoxing Xie ◽  
Gaoyun Xiong ◽  
Wenjun Chen ◽  
Hongdan Fu ◽  
Mingqian Li ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Nasopharyngeal Carcinoma ◽  
Cell Apoptosis ◽  
Inhibitory Effect ◽  
Akt Pathway ◽  
Migration And Invasion ◽  
Inhibitory Effects ◽  
Protein Levels ◽  
Flow Cytometric ◽  
Phosphoinositide 3 Kinase

FOXD3 has been found previously to positively regulate miR-26b, a tumor inhibitor of nasopharyngeal carcinoma (NPC). However, FOXD3’s precise function and associated mechanism of action in NPC have not yet been investigated. In this study, the expression of FOXD3 mRNA and protein was evaluated using RT-qPCR, western blotting, and immunohistochemistry. Protein levels involved in the phosphoinositide 3-kinase – protein kinase B (PI3K–Akt) pathway were assessed by western blot, and cell proliferation was determined by MTT and colony forming assays. Additionally, cell apoptosis was assessed by flow cytometric assay. Finally, the migration and invasion capabilities of the NPC cells were determined using wound healing and Transwell assays. We found that FOXD3 levels were relatively low in NPC tissue and cells, while an increase caused the inhibition of the PI3K–Akt pathway. Functional experiments found that overexpression of FOXD3 suppressed cell proliferation, migration, and invasion and enhanced cell apoptosis in NPC C6661 cells. IGF-1, an activator of the PI3K–Akt pathway, reversed the inhibitory effect of FOXD3. Furthermore, we found upregulation of the PI3K–Akt pathway and upregulation of the inhibitory effects of FOXD3 on C6661 cellular activities. In conclusion, FOXD3 negatively affected the PI3K–Akt pathway to restrain the processes involved in C6661 cell pathology. These findings further exposed the function and downstream axis of FOXD3 in NPC and displayed a promising new target for NPC therapy.

scholarly journals BAG3 contributes to HGF-mediated cell proliferation, migration, and invasion via the Egr1 pathway in gastric cancer

2018 ◽  
Vol 105 (1) ◽  
pp. 63-75
Author(s):  
Jae Chang Lee ◽  
Sung Ae Koh ◽  
Kyung Hee Lee ◽  
Jae-Ryong Kim
Keyword(s):  
Gastric Cancer ◽  
Cell Proliferation ◽  
Cell Invasion ◽  
Molecular Mechanisms ◽  
Migration And Invasion ◽  
Human Gastric Cancer ◽  
Protein Levels ◽  
Dependent Pathway

Introduction: Bcl2-associated athanogene 3 (BAG3) is elevated in several types of cancers. However, the role of BAG3 in progression of gastric cancer is unknown. Therefore, the present study aims to find out the role of BAG3 in hepatocyte growth factor (HGF)–mediated tumor progression and the molecular mechanisms by which HGF regulates BAG3 expression. Methods: BAG3 mRNA and protein were measured using reverse transcription polymerase chain reaction and Western blot in the 2 human gastric cancer cell lines, NUGC3 and MKN28, treated with or without HGF. The effects of BAG3 knockdown on cell proliferation, cell invasion, and apoptosis were analyzed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, the in vitro 2-chamber invasion assay, and flow cytometry in BAG3 short hairpin RNA (shRNA)–transfected cells and control cells. The signaling pathways involved in BAG3 that are regulated by HGF were analyzed. The chromatin immunoprecipitation assay was used to determine binding of Egr1 to the BAG3 promoter. Results: BAG3 mRNA and protein levels were increased following treatment with HGF. HGF-mediated BAG3 upregulation increased cell proliferation and cell invasion; however, it decreased apoptosis. HGF-mediated BAG3 upregulation is regulated by an ERK and Egr1-dependent pathway. BAG3 may have an important role in HGF-mediated cell proliferation and metastasis in gastric cancer through an ERK and Egr1-dependent pathway. Conclusion: This pathway may provide novel therapeutic targets and provide information for further identification of other targets of therapeutic significance in gastric cancer.

scholarly journals IcarisideII facilitates the differentiation of ADSCs to SCs via let-7i/STAT3 axis to preserve erectile function

2019 ◽  
Vol 52 (1) ◽  
Author(s):  
Pingyu Ge ◽  
Yinxue Guo ◽  
Jun Shen
Keyword(s):  
Cell Proliferation ◽  
Erectile Function ◽  
Molecular Mechanisms ◽  
Therapeutic Option ◽  
Luciferase Reporter ◽  
Dependent Manner ◽  
Regulatory Relationship ◽  
Rat Models ◽  
Protein Levels ◽  
Dose Dependent

Abstract Background IcarisideII (ICAII) could promote the differentiation of adipose tissue-derived stem cells (ADSCs) to Schwann cells (SCs), leading to improvement of erectile function (EF) and providing a realistic therapeutic option for the treatment of erectile dysfunction (ED). However, the underlying molecular mechanisms of ADSCs and ICAII in this process remain largely unclear. Methods ADSCs were treated with different concentrations of ICAII. Cell proliferation was determined by MTT assay. qRT-PCR and western blot were performed to detect expressions of SCs markers, signal transducer and activator of transcription-3 (STAT3), and microRNA-let-7i (let-7i). Luciferase reporter assay was conducted to verify the regulatory relationship between let-7i and STAT3. The detection of intracavernosal pressure (ICP) and the ratio of ICP/mean arterial pressure (MAP) were used to evaluate the EF in bilateral cavernous nerve injury (BCNI) rat models. Results ICAII promoted cell proliferation of ADSCs in a dose-dependent manner. The mRNA and protein levels of SCs markers were increased by ICAII treatment in a dose-dependent manner in ADSCs. Moreover, let-7i was significantly decreased in ICAII-treated ADSCs and upregulation of let-7i attenuated ICAII-induced promotion of SCs markers. In addition, STAT3 was a direct target of let-7i and upregulated in ICAII-treated ADSCs. Interestingly, overexpression of STAT3 abated the let-7i-mediated inhibition effect on differentiation of ADSCs to SCs and rescued the ICAII-mediated promotion effect on it. Besides, combination treatment of ADSCs and ICAII preserved the EF of BCNI rat models, which was undermined by let-7i overexpression. Conclusion ICAII was effective for preserving EF by promoting the differentiation of ADSCs to SCs via modulating let-7i/STAT3 pathway.

scholarly journals Overexpression of DDR1 Promotes Migration, Invasion, Though EMT-Related Molecule Expression and COL4A1/DDR1/MMP-2 Signaling Axis

2020 ◽  
Vol 19 ◽  
pp. 153303382097327
Author(s):  
Xin Xie ◽  
Hongchao He ◽  
Ning Zhang ◽  
Xiaojing Wang ◽  
Wenbin Rui ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Molecular Mechanisms ◽  
Mrna Level ◽  
Migration And Invasion ◽  
Rt Pcr ◽  
Protein Levels ◽  
Signaling Axis ◽  
Slug Expression ◽  
Mrna And Protein Expression

Purpose: Discoidin domain receptor 1 (DDR1) belongs to a novel class of receptor tyrosine kinases. Previous evidence indicates that DDR1 overexpression promotes the aggressive growth of bladder cancer (BC) cells. This study aimed to investigate the molecular mechanisms by which DDR1 influences BC. Methods: DDR1 was transfected into human BC RT4 cells. DDR1, COL4A1, and MMP-2 expression in 30 BC tissues and paired adjacent tissues were examined by real-time polymerase chain reaction (RT-PCR) and immunohistochemistry. Transwell assays were conducted to determine cell migration and invasion. RT-PCR and western blot (WB) were also used to measure the DDR1, COL4A1, MMP-2, and EMT-related gene (ZEB1 and SLUG) expression in RT4 cells after DDR1 overexpression. Results: COL4A1 and MMP-2 interacted with DDR1 in the PPI network. RT-PCR and immunohistochemistry results showed that both mRNA and protein levels of DDR1 and COL4A1 were significantly increased in BC tissue, while the expression of MMP-2 was increased only at the mRNA level ( P < 0.05). Overexpression of DDR1 in RT4 cells significantly promoted their migratory and invasive capabilities in vitro ( P < 0.05). Moreover, overexpression of DDR1 in RT4 cells increased the mRNA and protein expression of ZEB1, SLUG, COL4A1, and MMP-2 ( P < 0.01). DDR1-mediated migration and invasion of RT4 cells were reversed after COL4A1-siRNA treatment. Conclusion: DDR1 may be a potential therapeutic target in BC patients.

scholarly journals Phosphoinositide 3-Kinase C2β Regulates Cytoskeletal Organization and Cell Migration via Rac-dependent Mechanisms

2006 ◽  
Vol 17 (9) ◽  
pp. 3729-3744 ◽  
Author(s):  
Roy M. Katso ◽  
Olivier E. Pardo ◽  
Andrea Palamidessi ◽  
Clemens M. Franz ◽  
Marin Marinov ◽  
...  
Keyword(s):  
Cell Migration ◽  
Molecular Mechanisms ◽  
Egf Receptor ◽  
Human Tumor ◽  
Class Ii ◽  
Dominant Negative ◽  
Class I ◽  
Membrane Ruffling ◽  
And Migration ◽  
Phosphoinositide 3 Kinase

Receptor-linked class I phosphoinositide 3-kinases (PI3Ks) induce assembly of signal transduction complexes through protein–protein and protein–lipid interactions that mediate cell proliferation, survival, and migration. Although class II PI3Ks have the potential to make the same phosphoinositides as class I PI3Ks, their precise cellular role is currently unclear. In this report, we demonstrate that class II phosphoinositide 3-kinase C2β (PI3KC2β) associates with the Eps8/Abi1/Sos1 complex and is recruited to the EGF receptor as part of a multiprotein signaling complex also involving Shc and Grb2. Increased expression of PI3KC2β stimulated Rac activity in A-431 epidermoid carcinoma cells, resulting in enhanced membrane ruffling and migration speed of the cells. Conversely, expression of dominant negative PI3KC2β reduced Rac activity, membrane ruffling, and cell migration. Moreover, PI3KC2β-overexpressing cells were protected from anoikis and displayed enhanced proliferation, independently of Rac function. Taken together, these findings suggest that PI3KC2β regulates the migration and survival of human tumor cells by distinct molecular mechanisms.

scholarly journals Cigarette Smoke Extract Stimulates Rat Pulmonary Artery Smooth Muscle Cell Proliferation via PKC-PDGFB Signaling

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Ai-ping Xing ◽  
Yong-cheng Du ◽  
Xiao-yun Hu ◽  
Jian-ying Xu ◽  
Huan-ping Zhang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Cigarette Smoke ◽  
Cell Cycle Progression ◽  
Molecular Mechanisms ◽  
Cigarette Smoke Extract ◽  
Direct Role ◽  
Protein Levels ◽  
Pulmonary Artery Smooth Muscle

Accumulating evidence suggests a direct role for cigarette smoke in pulmonary vascular remodeling, which contributes to the development of pulmonary hypertension. However, the molecular mechanisms underlying this process remain poorly understood. Platelet-derived growth factor (PDGF) is a potential mitogen and chemoattractant implicated in several biological processes, including cell survival, proliferation, and migration. In this study, we investigated the effect of cigarette smoke extract (CSE) on cell proliferation of rat pulmonary artery smooth muscle cells (rPASMCs). We found that stimulation of rPASMCs with CSE significantly increased cell proliferation and promoted cell cycle progression from G1 phase to the S and G2 phases. CSE treatment also significantly upregulated the mRNA and protein levels of PDGFB and PDGFRβ. Our study also revealed that Rottlerin, an inhibitor of PKCδsignaling, prevented CSE-induced cell proliferation, attenuated the increase of S and G2 phase populations induced by CSE treatment, and downregulated PDGFB and PDGFRβmRNA and protein levels in rPASMCs exposed to CSE. Collectively, our data demonstrated that CSE-induced cell proliferation of rPASMCs involved upregulation of the PKCδ-PDGFB pathway.

scholarly journals Combination of CS2164 and Venetoclax Shows Synergistic Antitumor Effect in High-Grade B-Cell Lymphomas with ConcomitantMYCandBCL2Rearrangements

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 41-41
Author(s):  
Manman Deng ◽  
Delin Yuan ◽  
Genhong Li ◽  
Yuelong Jiang ◽  
Qinwei Chen ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
B Cell ◽  
Molecular Mechanisms ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
High Grade ◽  
Specific Patient ◽  
Bcl2 Family ◽  
Mitochondrial Membrane Depolarization ◽  
Orally Active

High-grade B-cell lymphoma with concurrentMYCandBCL2rearrangements (HGBCL-DHL) is a rare and aggressive B-cell disorder with a high likelihood of nonresponsiveness to the front-line immunochemotherapy. Patients with HGBCL-DHL who develop a recurrent or progressive disease have limited effective therapeutics and show very poor clinical outcomes. Therefore, it calls for the development of novel targeted therapies for this specific patient populations. In this study, we showed that combination of BCL2 inhibitor venetoclax and CS2164, a novel orally active multitarget inhibitor, is a potent therapeutic strategy against HGBCL-DHL in the preclinical setting. BCL2rearrangement, a hallmark feature of HGBCL-DHL, often results in increased BCL2 protein that counteracts the proapoptotic proteins of BCL2 family, and thus blocks cell death. BCL2 blockage with venetoclax shows promising clinical responses in various human malignancies. However, resistance to venetoclax takes place following its continuous administration, suggesting that venetoclax should combine with other agents to prevent disease progression. CS2164 is originally developed by China and designed to perturb three key characteristics of neoplasms: tumor angiogenesis, cell mitosis and chronic inflammation. Our previous study demonstrated that CS2164 exerted potently antilymphoma activities in MYC-driven lymphomas, providing evidence that CS2164 could potentiate the effect of venetoclax for MYC/BCL2 driven HGBCL-DHL. In the present work, we first observed that both venetoclax and CS2164 as single agent reduced the capability of cell proliferation in HGBCL-DHL cell lines. Next, we found that CS2164 synergized with venetoclax to suppress cell proliferation and trigger cell apoptosis in HGBCL-DHLin vitro. More importantly, when compared with each single drug groups, coadministration of venetoclax and CS2164 resulted in superior suppression of HGBCL-DHL cell growth and remarkably abrogated tumor burden in a HGBCL-DHL-xenografted mouse model. The synergistic lethality of venetoclax and CS2164 towards HGBCL-DHL cells was associated with the modulation of multiple molecular mechanisms. The underlying mechanisms for the synergy of the two drugs included the blockade of Rad51 recombinase-dependent DNA repair, the perturbation of the delicate balance of BCL2 family proteins that induced mitochondrial membrane depolarization and subsequently led to the proapoptotic effect, as well as the inhibition of PI3K/AKT/mTOR pathway and MYC expression. In summary, these findings suggest that the regimen of CS2164 and venetoclax combination is highly effective to eliminate HGBCL-DHL cellsin vitroandin vivoand thus provide a rational treatment paradigm to strip HGBCL-DHL of its protection fromMYCandBCL2rearrangements. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: CS2164 originally developed by China is a novel orally active multitarget inhibitor that is evaluating in clinical trials against multiple solid tumors.

scholarly journals Genistein Inhibits Human Colorectal Cancer Growth and Suppresses MiR-95, Akt and SGK1

2015 ◽  
Vol 35 (5) ◽  
pp. 2069-2077 ◽  
Author(s):  
Jian Qin ◽  
Jia Xin Chen ◽  
Zhou Zhu ◽  
Jia An Teng
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Molecular Mechanisms ◽  
Xenograft Model ◽  
Inhibitory Effect ◽  
Protein Levels ◽  
Phosphorylated Akt ◽  
Hct 116 ◽  
Hct 116 Cells

Background: Genistein, a major isoflavonoid isolated from dietary soybean, has been shown to suppress the growth of several cancers through modulation of various pathways. However, the molecular mechanisms by which genistein elicit its effects on colorectal cancer (CRC) cells have not been fully elucidated. In this study, we aimed to investigate the anti-tumor activities of genistein on CRC and its potential mechanism. Methods: Effects of genistein on the cell proliferation were tested in HCT-116 cells by MTT assay, and apoptosis was measured by Flow cytometry. Real-time PCR was also used to evaluate the regulation of genistein on miR-95, Akt and SGK1 expression. The protein levels of total Akt (T-Akt), and phosphorylated Akt (P-Akt) were assessed by western blot. A nude mice xenograft model was employed to determine whether genistein could have an anti-tumor effect on CRC in vivo. Results: We found that treatment of HCT-116 cells with genistein caused an inhibition of cell proliferation and induction of apoptosis. Meanwhile, genistein down-regulated the mRNA expression of Akt, SGK1 and miR-95, and inhibited the phosphorylation of Akt in HCT-116 cells. The experiment in vivo also showed that genistein significantly suppressed the growth of mouse xenograft tumor. Conclusion: This study demonstrates that genistein has an inhibitory effect on CRC involved in reducing miR-95, Akt and SGK1, offering novel insights into the mechanisms of genistein therapeutic actions.

scholarly journals Association Between C1q/TNF-Related Protein-1 Levels in Human Plasma and Epicardial Adipose Tissues and Congestive Heart Failure

2017 ◽  
Vol 42 (5) ◽  
pp. 2130-2143 ◽  
Author(s):  
Ying Yang ◽  
Si Liu ◽  
Rong-Yi Zhang ◽  
Hui Luo ◽  
Ling Chen ◽  
...  
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Molecular Mechanisms ◽  
Mrna Level ◽  
Mitogen Activated Protein Kinase ◽  
Mrna Levels ◽  
Related Protein ◽  
Tissue Samples ◽  
Protein Levels ◽  
Mitogen Activated Protein

Background/Aims: C1q and tumour necrosis factor-related protein 1 (CTRP1) possesses anti-atherogenic and anti-inflammatory effects. This study investigated whether the CTRP1 levels in the plasma and epicardial adipose tissue (EAT) were associated with congestive heart failure (CHF) and to disclose possible molecular mechanisms. Methods: Plasma and tissue samples were obtained from subjects with or without CHF. Plasma levels of CTRP1 were measured by ELISA. The mRNA levels of CTRP1 and inflammatory cytokines were detected by RT-PCR. The protein levels of CTRP1, aldosterone synthase (CYP11B2) and mitogen-activated protein kinase were examined by Western blotting. Results: The levels of CTRP1 in the plasma and EAT were higher in the CHF patients than those in the controls. There were no differences in the CTRP1 levels in cardiomyocytes between the CHF group and the non-CHF group. An exploratory survival analysis showed that higher CTRP1 values at admission were associated with a worse prognosis after discharge. CTRP1 increased the IL-6 mRNA level in H295R cells. CTRP1 recruited ERK1/2 and Jak-2 for aldosterone release by modulating the CYP11B2 protein level, and brain natriuretic peptide repressed the CTRP1-induced aldosterone release through the JAK2-STAT3 signalling pathways. Conclusion: The CTRP1 levels in the plasma and EAT were increased in the CHF patients. CTRP1 is involved in the pathogenesis of CHF by modulating IL-6 levels and aldosterone release.

scholarly journals LncRNA NEAT1 promotes endometrial cancer cell proliferation, migration and invasion by regulating the miR-144-3p/EZH2 axis

2019 ◽  
Vol 53 (4) ◽  
pp. 434-442 ◽  
Author(s):  
Wei Wang ◽  
Liang Ge ◽  
Xiao-Juan Xu ◽  
Ting Yang ◽  
Yue Yuan ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Endometrial Cancer ◽  
Molecular Mechanisms ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Non Coding Rna ◽  
Ishikawa Cells ◽  
Ec Cells ◽  
Proliferation And Invasion

Abstract Background Endometrial cancer (EC) is one of the most common gynaecological tumours in the worldwide. Long non-coding RNA (lncRNA) nuclear enriched abundant transcript 1 (NEAT1) promotes cell proliferation, migration and invasion in EC cells. However, the molecular mechanisms of NEAT1 in EC have not been fully clarified. We conducted this study to reveal the function of NEAT1 in EC tissues and cell lines. Materials and methods Cancer and adjacent tissues were collected from EC patients. HEC-1A and Ishikawa cells were cultured in vitro. NEAT1 expression was downregulated by transfecting small hairpin RNA (shRNA) and miR-144-3p was overexpressed by transfecting miR-144-3p mimics. Cell proliferation was detected by MTT assay and colony formation assay. Cell migration and invasion abilities were assessed by transwell assay. A dual-luciferase reporter assay was used to verify the relationship among NEAT1, EZH2, and miR-144-3p. The expression level of EZH2 was measured by Western blot and qPCR. Results NEAT1 was highly expressed in EC tissues and cells. Knockdown of NEAT1 inhibited the proliferation, migration and invasion of EC cells. Additionally, NEAT1 acted as a ceRNA of miR-144-3p, leading to EZH2 upregulation. Overexpression of miR-144-3p suppressed the proliferation and invasion of EC cells. Conclusions NEAT1 promotes EC cells proliferation and invasion by regulating the miR-144-3p/EZH2 axis.

Sign in / Sign up

Export Citation Format

Share Document