Chemokine CCL24 promotes the growth and invasiveness of trophoblasts through ERK1/2 and PI3K signaling pathways in human early pregnancy

Chemokine CCL24, acting through receptor CCR3, is a potent chemoattractant for eosinophil in allergic diseases and parasitic infections. We recently reported that CCL24 and CCR3 are co-expressed by trophoblasts in human early pregnant uterus. Here we prove with evidence that steroid hormones estradiol (E), progesterone (P), and human chorionic gonadotropin (hCG), as well as decidual stromal cells (DSCs) could regulate the expression of CCL24 and CCR3 of trophoblasts. We further investigate how trophoblast-derived CCL24 mediates the function of trophoblasts in vitro, and conclude that CCL24/CCR3 promotes the proliferation, viability and invasiveness of trophoblasts. In addition, analysis of the downstream signaling pathways of CCL24/CCR3 show that extracellular signal-regulated kinases (ERK1/2) and phosphoinositide 3-kinase (PI3K) pathways may contribute to the proliferation, viability and invasiveness of trophoblasts by activating intracellular molecules Ki67 and matrix metallopeptidase 9 (MMP9). However, we did not observe any inhibitory effect on trophoblasts when blocking c-Jun N-terminal kinase (JNK) or p38 pathways. In conclusion, our data suggests that trophoblast-derived CCL24 at the maternal-fetal interface promotes trophoblasts cell growth and invasiveness by ERK1/2 and PI3K pathways. Meanwhile, pregnancy-related hormones (P and hCG), as well as DSCs could up-regulate CCL24/CCR3 expression in trophoblasts, which may indirectly influence the biological functions of trophoblasts. Thus, our results provide a possible explanation for the growth and invasion of trophoblasts in human embryo implantation.

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Receptor Tyrosine Kinases and Their Signaling Pathways as Therapeutic Targets of Curcumin in Cancer

Frontiers in Pharmacology ◽

10.3389/fphar.2021.772510 ◽

2021 ◽

Vol 12 ◽

Author(s):

Sareshma Sudhesh Dev ◽

Syafiq Asnawi Zainal Abidin ◽

Reyhaneh Farghadani ◽

Iekhsan Othman ◽

Rakesh Naidu

Keyword(s):

Signaling Pathways ◽

Cancer Progression ◽

Tyrosine Kinases ◽

Receptor Tyrosine Kinases ◽

Surface Proteins ◽

Downstream Signaling ◽

Anti Cancer ◽

Rtk Inhibitors

Receptor tyrosine kinases (RTKs) are transmembrane cell-surface proteins that act as signal transducers. They regulate essential cellular processes like proliferation, apoptosis, differentiation and metabolism. RTK alteration occurs in a broad spectrum of cancers, emphasising its crucial role in cancer progression and as a suitable therapeutic target. The use of small molecule RTK inhibitors however, has been crippled by the emergence of resistance, highlighting the need for a pleiotropic anti-cancer agent that can replace or be used in combination with existing pharmacological agents to enhance treatment efficacy. Curcumin is an attractive therapeutic agent mainly due to its potent anti-cancer effects, extensive range of targets and minimal toxicity. Out of the numerous documented targets of curcumin, RTKs appear to be one of the main nodes of curcumin-mediated inhibition. Many studies have found that curcumin influences RTK activation and their downstream signaling pathways resulting in increased apoptosis, decreased proliferation and decreased migration in cancer both in vitro and in vivo. This review focused on how curcumin exhibits anti-cancer effects through inhibition of RTKs and downstream signaling pathways like the MAPK, PI3K/Akt, JAK/STAT, and NF-κB pathways. Combination studies of curcumin and RTK inhibitors were also analysed with emphasis on their common molecular targets.

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The Antitumor Effect of Gekko Sulfated Glycopeptide by Inhibiting bFGF-Induced Lymphangiogenesis

BioMed Research International ◽

10.1155/2016/7396392 ◽

2016 ◽

Vol 2016 ◽

pp. 1-9 ◽

Cited By ~ 5

Author(s):

Xiu-Li Ding ◽

Ya-Nan Man ◽

Jian Hao ◽

Cui-Hong Zhu ◽

Chang Liu ◽

...

Keyword(s):

Immunohistochemical Staining ◽

Antitumor Effect ◽

Inhibitory Effect ◽

Tube Formation ◽

Fibroblast Growth ◽

Lymphatic Endothelial Cells ◽

Tumor Lymphangiogenesis ◽

Extracellular Signal

Objective. To study the antilymphangiogenesis effect of Gekko Sulfated Glycopeptide (GSPP) on human lymphatic endothelial cells (hLECs).Methods. MTS was conducted to confirm the antiproliferation effect of GSPP on hLECs; flow cytometry was employed to detect hLECs cycle distribution; the antimigration effect of GSPP on hLECs was investigated by wound healing experiment and transwell experiment; tube formation assay was used to examine its inhibitory effect on the lymphangiogenesis; western blotting was conducted to detect the expression of extracellular signal-regulated kinase1/2 (Erk1/2) and p-Erk1/2 after GSPP and basic fibroblast growth factor (bFGF) treatment. Nude mice models were established to investigate the antitumor effect of GSPP in vivo. Decreased lymphangiogenesis caused by GSPP in vivo was verified by immunohistochemical staining.Results. In vitro, GSPP (10 μg/mL, 100 μg/mL) significantly inhibited bFGF-induced hLECs proliferation, migration, and tube-like structure formation (P<0.05) and antagonized the phosphorylation activation of Erk1/2 induced by bFGF. In vivo, GSPP treatment (200 mg/kg/d) not only inhibited the growth of colon carcinoma, but also inhibited the tumor lymphangiogenesis.Conclusion. GSPP possesses the antitumor ability by inhibiting bFGF-inducing lymphangiogenesis in vitro and in vivo, which may further inhibit tumor lymphatic metastasis.

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Involvement of MEK/ERK1/2 and PI3K/Akt Pathways in the Refractory Behavior of GH3B6 Pituitary Tumor Cells to the Inhibitory Effect of TGFβ1

Endocrinology ◽

10.1210/en.2014-1070 ◽

2014 ◽

Vol 156 (2) ◽

pp. 534-547 ◽

Cited By ~ 9

Author(s):

Juan Pablo Petiti ◽

Liliana del Valle Sosa ◽

María Eugenia Sabatino ◽

Alicia Maldré Vaca ◽

Silvina Gutiérrez ◽

...

Keyword(s):

Tumor Cells ◽

Cross Talk ◽

Pituitary Tumor ◽

Direct Interaction ◽

Poor Response ◽

Inhibitory Effect ◽

Pi3k Inhibitors ◽

Transmission Electron ◽

Extracellular Signal ◽

Phosphoinositide 3 Kinase

Pituitary tumor cells have a poor response to the growth inhibitory effect of TGFβ1, possibly resulting from the cross talk of TGFβ/Smads signal with other signaling pathways, an undescribed mechanism in these tumoral cells. To address this hypothesis, we investigated whether the mitogen-activated extracellular signal-regulated kinase (MEK)/ERK1/2 and phosphoinositide-3 kinase/protein kinase B (PI3K/Akt) pathways were able to regulate the antimitogenic effect of TGFβ1 on GH3B6 cells. TGFβ1 treatment decreased the cell proliferation and induced an activation of mothers against decapentaplegic homolog 2/3 (Smad2/3), effects that were potentiated by MEK and PI3K inhibitors, thus indicating the existence of a cross talk between TGFβ1/Smad with the MEK/ERK1/2 or PI3K/Akt pathways. In addition, through immunoprecipitation assays, a direct interaction was observed between Smad2/3-ERK1/2 and Smad2/3-Akt, which decreased when the GH3B6 cells were incubated with TGFβ1 in the presence of MEK or PI3K inhibitors, thereby suggesting that the ERK1/2- and Akt-activated states were involved. These Smad2/3-ERK1/2 and Smad2/3-Akt associations were also confirmed by confocal and transmission electron microscopy. These findings indicate that the TGFβ1-antimitogenic effect in GH3B6 cells was attenuated by the MEK/ERK1/2 and PI3K/Akt pathways via modulating Smad2/3 phosphorylation. This molecular mechanism could explain in part the refractory behavior of pituitary tumor cells to the inhibitory effect of TGFβ1.

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Leptin Upregulates the Expression of β3-Integrin, MMP9, HB-EGF, and IL-1β in Primary Porcine Endometrium Epithelial Cells In Vitro

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph17186508 ◽

2020 ◽

Vol 17 (18) ◽

pp. 6508

Author(s):

Hongfang Wang ◽

Jinlian Fu ◽

Aiguo Wang

Keyword(s):

Signaling Pathways ◽

Embryo Implantation ◽

Mapk Signaling ◽

Dependent Manner ◽

Reproductive Disorders ◽

Β3 Integrin ◽

Epithelium Cells ◽

Dose Dependent

Obesity has become a global health problem. Research suggests that leptin, a hormone that responds to fat deposition, may be involved in mammalian reproduction; however, its precise role in embryo implantation is poorly understood. Here, primary porcine endometrium epithelium cells (PEECs) were cultured in vitro and used to evaluate the regulatory role of different leptin levels on β3-integrin, MMP9, HB-EGF, and IL-1β, which are, respectively, involved in four critical steps of embryo implantation. Results showed that only 0.01 nM leptin significantly improved β3-integrin mRNA expression (p < 0.05). MMP9 and HB-EGF mRNA expressions were upregulated by 0.10–10.00 nM leptin (p < 0.05). The IL-1β expression level was only increased by 10.00 nM leptin (p < 0.05). β3-integrin, MMP9, HB-EGF, and IL-1β mRNA and protein have a similar fluctuant response to increased leptin. Leptin’s influence on β3-integrin, MMP9, HB-EGF, and IL-1β disappeared when the JAK2, PI(3)K, or MAPK signaling pathways were blocked, respectively. In conclusion, leptin affected porcine implantation by regulating the expression of β3-integrin, MMP9, HB-EGF, and IL-1β in a dose-dependent manner. The signaling pathways of JAK2, PI(3)K, and MAPK may participate in this regulatory process. These findings will contribute to further understanding the mechanisms of reproductive disorders in obesity.

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Pharmacological Modulation of Ubiquitin-Proteasome Pathways in Oncogenic Signaling

International Journal of Molecular Sciences ◽

10.3390/ijms222111971 ◽

2021 ◽

Vol 22 (21) ◽

pp. 11971

Author(s):

Anmol Sharma ◽

Heena Khan ◽

Thakur Gurjeet Singh ◽

Amarjot Kaur Grewal ◽

Agnieszka Najda ◽

...

Keyword(s):

Signaling Pathways ◽

Cell Cycle Control ◽

In Vivo Studies ◽

Oncogenic Signaling ◽

Aberrant Expression ◽

Downstream Signaling ◽

Ubiquitin Proteasome ◽

Progressive Growth

The ubiquitin-proteasome pathway (UPP) is involved in regulating several biological functions, including cell cycle control, apoptosis, DNA damage response, and apoptosis. It is widely known for its role in degrading abnormal protein substrates and maintaining physiological body functions via ubiquitinating enzymes (E1, E2, E3) and the proteasome. Therefore, aberrant expression in these enzymes results in an altered biological process, including transduction signaling for cell death and survival, resulting in cancer. In this review, an overview of profuse enzymes involved as a pro-oncogenic or progressive growth factor in tumors with their downstream signaling pathways has been discussed. A systematic literature review of PubMed, Medline, Bentham, Scopus, and EMBASE (Elsevier) databases was carried out to understand the nature of the extensive work done on modulation of ubiquitin-proteasome pathways in oncogenic signaling. Various in vitro, in vivo studies demonstrating the involvement of ubiquitin-proteasome systems in varied types of cancers and the downstream signaling pathways involved are also discussed in the current review. Several inhibitors of E1, E2, E3, deubiquitinase enzymes and proteasome have been applied for treating cancer. Some of these drugs have exhibited successful outcomes in in vivo studies on different cancer types, so clinical trials are going on for these inhibitors. This review mainly focuses on certain ubiquitin-proteasome enzymes involved in developing cancers and certain enzymes that can be targeted to treat cancer.

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Anti-Allergy Potential of Averrhoa bilimbi Linn. Fruit Water Extract Shown by Its Suppressive Effect on the Degranulation of RBL-2H3 Cells

Journal of Functional Food and Nutraceutical ◽

10.33555/jffn.v2i2.62 ◽

2021 ◽

pp. 81-88

Author(s):

William Halim Santoso ◽

Momoko Ishida ◽

Kosuke Nishi ◽

Takuya Sugahara ◽

Agus Budiawan Naro Putra

Keyword(s):

Calcium Concentration ◽

Water Extract ◽

Allergic Diseases ◽

Suppressive Effect ◽

Inhibitory Effect ◽

Current Evidence ◽

Polyphenol Content ◽

Calcium Dependent ◽

Active Substances

Allergy rhinitis (AR), as reported by the World Allergy Organization (WAO), is one of the highest prevalence allergies affecting 10-30% of all adults and up to 40% of children. In Indonesia, current evidence showed that the prevalence of AR is increasing. Averrhoa bilimbi Linn. fruit (AF), or locally known as belimbing wuluh, has been scientifically proven to treat many diseases due to the abundant of polyphenol content which was shown to have the potential to treat allergies. Therefore, this study was aimed to investigate the anti-allergy potential of AF in vitro. The anti-allergy effect of Averrhoa bilimbi Linn. fruit water extract (AFWE) was examined using RBL-2H3 cells. At first, the cytotoxicity effect of AFWE was determined by WST-8 assay. The release of β-hexosaminidase by RBL-2H3 cells was also measured to evaluate degranulation suppression activity of AFWE. Lastly, calcium assay was employed to investigate the intracellular calcium concentration ([Ca2+]i). Results demonstrated that AFWE does not show any cytotoxicity at any given concentration. In addition, AFWE at 1.25 mg/mL showed sufficient inhibitory effect towards degranulation by RBL-2H3 cells. Moreover, the degranulation-suppressing activity of AFWE was resulted from the inhibition of calcium-dependent signaling pathways. Unfortunately, the properties of active substances from AFWE have not been investigated. To conclude, this study indicated that AFWE has potential as an alternative treatment for allergic diseases.

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Inhibition of cAMP/PKA/CREB Signaling Axis Improves Fibroblast Plasticity for Direct Cardiac Reprogramming

10.20944/preprints202104.0565.v1 ◽

2021 ◽

Author(s):

Emre Bektik ◽

Yu Sun ◽

Adrienne Dennis ◽

Phraew Sakon ◽

Dandan Yang ◽

...

Keyword(s):

Signaling Pathways ◽

Primary Cell Culture ◽

Myofibroblast Differentiation ◽

Camp Concentration ◽

Cultured Fibroblasts ◽

Downstream Signaling ◽

Upstream Regulator ◽

Reprogramming Efficiency ◽

Signaling Axis

Direct cardiac reprogramming of fibroblasts into induced cardiomyocytes (iCMs) is a promising approach but remains a challenging technology of regenerative medicine for damaged myocardium. Efforts have been focused on improving the efficiency by understanding fundamental mechanisms. One of the major challenges is that the plasticity of cultured fibroblast varies batch to batch with unknown mechanisms. Here, we noticed that a portion of in vitro cultured fibroblasts have been activated to differentiate into myofibroblasts, marked by the expression of αSMA, even in the primary cell culture of tissues. Both forskolin, which activates adenylyl cyclase and increases cAMP concentration, and TGFbeta inhibitor SB431542 can efficiently suppress myofibroblast differentiation of cultured fibroblasts. However, SB431542 improved but forskolin blocked iCM reprogramming of fibroblasts that were infected with retroviruses of Gata4, Mef2c and Tbx5 (GMT). Moreover, inhibitors of cAMP downstream signaling pathways, PKA or CREB-CBP, significantly improved the efficiency of iCM reprogramming. Consistently, inhibition of p38/MAPK, another upstream regulator of CREB-CBP, also improved reprogramming efficiency. We then investigated if inhibition of these signaling pathways in primary cultured fibroblast could improve their plasticity for reprogramming, and found that preconditioning of cultured fibroblasts with CREB-CBP inhibitor significantly improved the cellular plasticity of fibroblasts to be reprogrammed, yielding ~2-fold amount of reprogrammed iCMs compared to that of untreated control cells. In conclusion, suppression of cAMP/PKA/CREB signaling axis improves fibroblast plasticity for direct cardiac reprogramming.

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Colony-stimulating Factor-1 Receptor Utilizes Multiple Signaling Pathways to Induce Cyclin D2 Expression

Molecular Biology of the Cell ◽

10.1091/mbc.11.11.3835 ◽

2000 ◽

Vol 11 (11) ◽

pp. 3835-3848 ◽

Cited By ~ 41

Author(s):

Arunangsu Dey ◽

Hongyun She ◽

Leopold Kim ◽

Allan Boruch ◽

Deborah L. Guris ◽

...

Keyword(s):

Signaling Pathways ◽

Single Gene ◽

Inhibitory Effect ◽

Early Gene ◽

Erk Pathway ◽

Colony Stimulating Factor ◽

Signaling Mechanism ◽

Extracellular Signal ◽

Multiple Signaling ◽

Stimulating Factor

Colony-stimulating factor-1 (CSF-1) induces expression of immediate early gene, such as c-myc and c-fos and delayed early genes such as D-type cyclins (D1 and D2), whose products play essential roles in the G1 to S phase transition of the cell cycle. Little is known, however, about the cytoplasmic signal transduction pathways that connect the surface CSF-1 receptor to these genes in the nucleus. We have investigated the signaling mechanism of CSF-1-induced D2 expression. Analyses of CSF-1 receptor autophosphorylation mutants show that, although certain individual mutation has a partial inhibitory effect, only multiple combined mutations completely block induction of D2 in response to CSF-1. We report that at least three parallel pathways, the Src pathway, the MAPK/ERK kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway, and the c-myc pathway, are involved. Induction of D2 is partially inhibited in Src−/− bone marrow-derived macrophages and by Src inhibitor PP1 and is enhanced in v-Src-overexpressing cells. Activation of myc's transactivating activity selectively induces D2 but not D1. Blockade of c-myc expression partially blocks CSF-1-induced D2 expression. Complete inhibition of the MEK/ERK pathway causes 50% decrease of D2 expression. Finally, simultaneous inhibition of Src, MEK activation, and c-myc expression additively blocks CSF-1-induced D2 expression. This study indicates that multiple signaling pathways are involved in full induction of a single gene, and this finding may also apply broadly to other growth factor-inducible genes.

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Ethanol Modulates the Growth of Human Breast Cancer Cells In Vitro

Experimental Biology and Medicine ◽

10.1177/153537020222700406 ◽

2002 ◽

Vol 227 (4) ◽

pp. 260-265 ◽

Cited By ~ 35

Author(s):

Ernest B. Izevbigie ◽

Stephen I. Ekunwe ◽

Jenny Jordan ◽

Carolyn B. Howard

Keyword(s):

Cell Growth ◽

Signaling Pathways ◽

Cell Number ◽

Mapk Signaling ◽

Suitable Model ◽

Human Breast ◽

Extracellular Signal ◽

Mitogen Activated Protein ◽

Mcf 7

The role of ethanol or its metabolites on breast neoplasm has not been characterized. We hypothesized that ethanol may alter the growth rate of human breast tumor epithelial cells by modulating putative growth-promoting signaling pathways such as p44/42 mitogen-activated protein kinases (MAPKs). The MCF-7 cell line, considered a suitable model, was used in these studies to investigate the effects of ethanol on [3H]thymidine incorporation, cell number, and p44/42 MAPK activities in the presence or absence of a MAPK or extracellular signal-regulated kinase ERK-1, and (MEK1) inhibitor (PD098059). Treatment of MCF-7 cells with a physiologically relevant concentration of ethanol (0.3% or 65 mM) increased p44/42 activities by an average of 400% (P < 0.02), and subsequent cell growth by 200% (P < 0.05) in a MEK1 inhibitor (PD098059)-sensitive fashion, thus suggesting that the Ras/MEK/MAPK signaling pathways are crucial for ethanol-induced MCF-7 cell growth.

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Effects of Axotomy on Cultured Sensory Neurons of Aplysia: Long-Term Injury-Induced Changes in Excitability and Morphology Are Mediated by Different Signaling Pathways

Journal of Neurophysiology ◽

10.1152/jn.90539.2008 ◽

2008 ◽

Vol 100 (6) ◽

pp. 3209-3224 ◽

Cited By ~ 2

Author(s):

Supinder S. Bedi ◽

Diancai Cai ◽

David L. Glanzman

Keyword(s):

Signaling Pathways ◽

Sensory Neurons ◽

Specific Inhibitor ◽

Distinct Pattern ◽

Extracellular Signal ◽

Vitro Model ◽

Induced Changes ◽

And Control

To facilitate an understanding of injury-induced changes within the nervous system, we used a single-cell, in vitro model of axonal injury. Sensory neurons were individually dissociated from the CNS of Aplysia and placed into cell culture. The major neurite of some neurons was then transected (axotomized neurons). Axotomy in hemolymph-containing culture medium produced long-term hyperexcitability (LTH-E) and enhanced neuritic sprouting (long-term hypermorphogenesis [LTH-M]). Axotomy in the absence of hemolymph induced LTH-E, but not LTH-M. Hemolymph-derived growth factors may activate tyrosine receptor kinase (Trk) receptors in sensory neurons. To examine this possibility, we treated uninjured (control) and axotomized sensory neurons with K252a, an inhibitor of Trk receptor activity. K252a depressed the excitability of both axotomized and control neurons. K252a also produced a distinct pattern of arborizing outgrowth of neurites in both axotomized and control neurons. Protein kinase C (PKC) is an intracellular signal downstream of Trk; accordingly, we tested the effects of bisindolylmaleimide I (Bis-I), a specific inhibitor of PKC, on the axotomy-induced cellular changes. Bis-I blocked LTH-E, but did not disrupt LTH-M. Finally, because Trk activates the extracellular signal regulated kinase pathway in Aplysia sensory neurons, we examined whether this pathway mediates the injury-induced changes. Sensory neurons were axotomized in the presence of U0126, an inhibitor of mitogen-activated/extracellular receptor-regulated kinase. U0126 blocked the LTH-M due to axotomy, but did not impair LTH-E. Therefore distinct cellular signaling pathways mediate the induction of LTH-E and LTH-M in the sensory neurons.

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