Browse
Submit Data
Databases
API
Help

Dataset Information

20 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Inhibition of esophageal-carcinoma cell proliferation by genistein via suppression of JAK1/2-STAT3 and AKT/MDM2/p53 signaling pathways.

ABSTRACT: Esophageal carcinoma (EsC) is a clinically challenging neoplastic disease. Genistein, a natural isoflavone product, has anti-tumor properties. Through in vitro and in vivo studies, we found that genistein suppressed EsC cell proliferation in a time- and concentration-dependent manner. In addition, genistein markedly promoted apoptosis and arrested cell cycle at the G0/G1 phase in a concentration-dependent manner. Furthermore, high concentrations of genistein have no adverse effect on normal esophageal epithelial cells. Mechanistically, genistein treatment strikingly reduced the expression of cell cycle-associated genes, and up-regulated the expression of cell apoptosis-related genes in EsC cells. Additionally, genistein dramatically decreased epidermal growth factor receptor (EGFR) expression and attenuated its down-stream signaling molecules STAT3, MDM2, Akt and JAK1/2 phosphorylation, resulting in inhibited nuclear translocation of STAT3 and MDM2, thereby inhibiting the JAK1/2-STAT3 and AKT/MDM2/p53 signaling pathways. In xenograft nude mice, genistein administration strikingly impaired tumor growth in a dose-dependent manner. Moreover, similar disturbances in molecular mechanisms were observed in vivo. Taken together, genistein suppressed the JAK1/2-STAT3 and AKT/MDM2/p53 signaling pathways by decreasing EGFR expression, leading to cell apoptosis, cell cycle arrest, and proliferation inhibition in EsC cells. Our findings suggest that genistein may be a promising alternative adjuvant therapy for patients with EsC.

SUBMITTER: Gao J

PROVIDER: S-EPMC7185096 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

GCN5 Potentiates Glioma Proliferation and Invasion via STAT3 and AKT Signaling Pathways.

Project description:The general control of nucleotide synthesis 5 (GCN5), which is one kind of lysine acetyltransferases, regulates a number of cellular processes, such as cell proliferation, differentiation, cell cycle and DNA damage repair. However, its biological role in human glioma development remains elusive. In the present study, we firstly reported that GCN5 was frequently overexpressed in human glioma tissues and GCN5 was positively correlated with proliferation of cell nuclear antigen PCNA and matrix metallopeptidase MMP9. Meanwhile, down-regulation of GCN5 by siRNA interfering inhibited glioma cell proliferation and invasion. In addition, GCN5 knockdown reduced expression of p-STAT3, p-AKT, PCNA and MMP9 and increased the expression of p21 in glioma cells. In conclusion, GCN5 exhibited critical roles in glioma development by regulating cell proliferation and invasion, which suggested that GCN5 might be a potential molecular target for glioma treatment.

| S-EPMC4613287 | biostudies-literature

Mdm2 phosphorylation by Akt regulates the p53 response to oxidative stress to promote cell proliferation and tumorigenesis.

Project description:We have shown previously that phosphorylation of Mdm2 by ATM and c-Abl regulates Mdm2-p53 signaling and alters the effects of DNA damage in mice, including bone marrow failure and tumorigenesis induced by ionizing radiation. Here, we examine the physiological effects of Mdm2 phosphorylation by Akt, another DNA damage effector kinase. Surprisingly, Akt phosphorylation of Mdm2 does not alter the p53-mediated effects of ionizing radiation in cells or mice but regulates the p53 response to oxidative stress. Akt phosphorylation of Mdm2 serine residue 183 increases nuclear Mdm2 stability, decreases p53 levels, and prevents senescence in primary cells exposed to reactive oxidative species (ROS). Using multiple mouse models of ROS-induced cancer, we show that Mdm2 phosphorylation by Akt reduces senescence to promote KrasG12D-driven lung cancers and carcinogen-induced papilloma and hepatocellular carcinomas. Collectively, we document a unique physiologic role for Akt-Mdm2-p53 signaling in regulating cell growth and tumorigenesis in response to oxidative stress.

| S-EPMC7848548 | biostudies-literature

Plumbagin inhibits the proliferation and survival of esophageal cancer cells by blocking STAT3-PLK1-AKT signaling.

Project description:Esophageal squamous cell carcinoma (ESCC) is one of the deadliest cancers, and it requires novel treatment approaches and effective drugs. In the present study, we found that treatment with plumbagin, a natural compound, reduced proliferation and survival of the KYSE150 and KYSE450 ESCC cell lines in a dose-dependent manner in vitro. The drug also effectively inhibited the viability of primary ESCC cells from fresh biopsy specimens. Furthermore, plumbagin-induced mitotic arrest and massive apoptosis in ESCC cells. Notably, the drug significantly suppressed the colony formation capacity of ESCC cells in vitro and the growth of KYSE150 xenograft tumors in vivo. At the molecular level, we found that exposure to plumbagin decreased both polo-like kinase 1 (PLK1) and phosphorylated protein kinase B (p-AKT) expression in both ESCC cell lines. Enforced PLK1 expression in ESCC cells not only markedly rescued cells from plumbagin-induced apoptosis and proliferation inhibition but also restored the impaired AKT activity. Furthermore, signal transducer and activator of transcription 3 (STAT3), a transcription factor of PLK1, was also inactivated in plumbagin-treated ESCC cells; however, the overexpression of a constitutively activated STAT3 mutant, STAT3C, reinstated the plumbagin-elicited blockade of PLK1-AKT signaling in ESCC cells. Taken together, these findings indicate that plumbagin inhibits proliferation and potentiates apoptosis in human ESCC cells in vitro and in vivo. Plumbagin may exert these antitumor effects by abrogating STAT3-PLK1-AKT signaling, which suggests that plumbagin may be a novel, promising anticancer agent for the treatment of ESCC.

| S-EPMC5833725 | biostudies-literature

Hedgehog signaling overrides p53-mediated tumor suppression by activating Mdm2.

Project description:The hedgehog (Hh) signaling pathway regulates the development of many organs in mammals, and activation of this pathway is widely observed in human cancers. Although it is known that Hh signaling activates the expression of genes involved in cell growth, the precise role of the Hh pathway in cancer development is still unclear. Here, we show that constitutively activated mutants of Smoothened (Smo), a transducer of the Hh signaling pathway, inhibit the accumulation of the tumor suppressor protein p53. This inhibition was also observed in the presence of Hh ligand or with the overexpression of the transcription factors Gli1 and Gli2, downstream effectors of Smo, indicating that this inhibition is specific for the Hh pathway. We also report that Smo mutants augment p53 binding to the E3 ubiquitin-protein ligase Mdm2 and promote p53 ubiquitination. Furthermore, Hh signaling induced the phosphorylation of human Mdm2 protein on serines 166 and 186, which are activating phosphorylation sites of Mdm2. Smo mutants enhanced the proliferation of mouse embryonic fibroblasts (MEFs) while inducing a DNA-damage response. Moreover, Smo partially inhibited p53-dependent apoptosis and cell growth inhibition in oncogene-expressing MEFs. We also found that accumulation of p53 is inhibited by Hh signaling in several human cancer cell lines. Therefore, the Hh pathway may be a powerful accelerator of oncogenesis by activating cell proliferation and inhibiting the p53-mediated anti-cancer barrier induced by oncogenic stress.

| S-EPMC2290789 | biostudies-literature

The Synthetic ?-Nitrostyrene Derivative CYT-Rx20 Inhibits Esophageal Tumor Growth and Metastasis via PI3K/AKT and STAT3 Pathways.

Project description:The ?-nitrostyrene family have been implicated for anti-cancer property. However, the pharmacological role of ?-nitrostyrene in esophageal cancer remain unclear. Here, a ?-nitrostyrene derivative, CYT-Rx20, was synthesized and assessed for its anti-cancer activities and underlying mechanism in esophageal cancer. CYT-Rx20 induced cytotoxicity in esophageal cancer cells by promoting apoptosis through activation of caspase cascade and poly(ADP-ribose) polymerase (PARP) cleavage. Besides, CYT-Rx20 inhibited esophageal cancer cell migration and invasion by regulating the expression of epithelial to mesenchymal transition (EMT) markers. CYT-Rx20 decreased cell viability and migration through suppression of the PI3K/AKT and STAT3 pathways. Of note, the cytotoxicity and anti-migratory effect of CYT-Rx20 were enhanced by co-treatment with SC79 (AKT activator) or colivelin (STAT3 activator), suggesting the dependency of esophageal cancer cells on AKT and STAT3 for survival and migration, an oncogene addiction phenomenon. In xenograft tumor-bearing mice, CYT-Rx20 significantly reduced tumor growth of the implanted esophageal cancer cells accompanied by decreased Ki-67, phospho-AKT, and phospho-STAT3 expression. In orthotopic esophageal cancer mouse model, decreased tumor growth and lung metastasis with reduced Ki-67 and phospho-STAT3 expression were observed in mice treated with CYT-Rx20. Together, our results suggest that CYT-Rx20 is a potential ?-nitrostyrene-based anticancer compound against the tumor growth and metastasis of esophageal cancer.

| S-EPMC5119777 | biostudies-literature

miR302a inhibits the proliferation of esophageal cancer cells through the MAPK and PI3K/Akt signaling pathways.

Project description:MicroRNAs (miRNAs/miRs) are involved in the regulation of various types of cancer, either as oncogenes or tumor suppressors. miR302a has been reported that it could suppress tumor cell proliferation by inhibiting Akt in prostate cancer. The present study examined the effect of miR302a on proliferation and invasion in esophageal cancer cell lines. The expression levels of miR302a in esophageal cancer cell lines was determined by reverse transcription-polymerase chain reaction. Subsequently, miR302a mimics were transfected into esophageal cancer cells, and cell viability and invasion were assessed by MTT and Transwell assays. In addition, the effects of miR302a on the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathways were investigated by western blot analysis. The results revealed that miR302a expression was significantly decreased in the esophageal cancer cell lines compared with a healthy esophagus epithelium cell line. Upregulation of miR302a inhibited the proliferation and invasion of esophageal cancer cells, and decreased the phosphorylation of extracellular signal-regulated kinase 1/2 and Akt. Taken together, the results of the present study indicated that miR302a overexpression inhibited the proliferation and invasion of esophageal cancer cells through suppression of the MAPK and PI3K/Akt signaling pathways, indicating the potential value of miR302a as a treatment target for human esophageal cancer.

| S-EPMC5795869 | biostudies-literature

LIF negatively regulates tumour-suppressor p53 through Stat3/ID1/MDM2 in colorectal cancers.

Project description:Leukaemia inhibitory factor (LIF) has been recently identified as a p53 target gene, which mediates the role of p53 in maternal implantation under normal physiological conditions. Here we report that LIF is a negative regulator of p53; LIF downregulates p53 protein levels and function in human colorectal cancer (CRC) cells. The downregulation of p53 by LIF is mediated by the activation of Stat3, which transcriptionally induces inhibitor of DNA-binding 1 (ID1). ID1 upregulates MDM2, a key negative regulator of p53, and promotes p53 protein degradation. LIF is overexpressed in a large percentage of CRCs. LIF overexpression promotes cellular resistance towards chemotherapeutic agents in cultured CRC cells and colorectal xenograft tumours in a largely p53-dependent manner. Overexpression of LIF is associated with a poor prognosis in CRC patients. Taken together, LIF is a novel negative regulator of p53, overexpression of LIF is an important mechanism for the attenuation of p53, which promotes chemoresistance in CRCs.

| S-EPMC4203416 | biostudies-literature

Loss of FAM60A attenuates cell proliferation in glioma via suppression of PI3K/Akt/mTOR signaling pathways.

Project description:BackgroundGlioma is a common malignant tumor of the central nervous system with a high incidence and mortality. Family with sequence similarity 60 member A (FAM60A) is a new subunit of the Sin3 deacetylase complex. The clinical significance and biologic role of FAM60A in glioma remain unclear.MethodsThe expression of FAM60A in normal glial cells, glioma cells, and five-paired gliomas, and adjacent noncancerous tissues was quantified using real-time polymerase chain reaction (PCR) and western blotting. FAM60A protein expression in 179 archived, paraffin-embedded glioma samples was analyzed using immunohistochemistry. The roles of FAM60A in glioma cell proliferation and tumorigenicity were explored in vitro and in vivo. The underlying molecular mechanisms were elucidated using Western blot assay. Serum exosomal FAM60A levels of glioma patients were detected using electron microscopy, western blot, and real-time PCR.ResultsFAM60A expression was significantly up-regulated in glioma tissues and cell lines and positively associated with a worse outcome in glioma. Knockdown of FAM60A could inhibit glioma cell proliferation and tumorigenicity in vitro and in vivo. Besides, FAM60A expression was detectable in extracted serum exosomes with a higher expression in the glioma cancer group than in the normal group.ConclusionsLoss of FAM60A attenuates cell proliferation in glioma by suppressing PI3K/Akt/mTOR signaling pathways. Therefore, FAM60A may act as a prognostic biomarker and therapeutic target for glioma.

| S-EPMC8363885 | biostudies-literature

BMX/Etk promotes cell proliferation and tumorigenicity of cervical cancer cells through PI3K/AKT/mTOR and STAT3 pathways.

Project description:Bone marrow X-linked kinase (BMX, also known as Etk) has been reported to be involved in cell proliferation, differentiation, apoptosis, migration and invasion in several types of tumors, but its role in cervical carcinoma remains poorly understood. In this study, we showed that BMX expression exhibits a gradually increasing trend from normal cervical tissue to cervical cancer in situ and then to invasive cervical cancer tissue. Through BMX-IN-1, a potent and irreversible BMX kinase inhibitor, inhibited the expression of BMX, the cell proliferation was significantly decreased. Knockdown of BMX in HeLa and SiHa cervical cancer cell lines using two different silencing technologies, TALEN and shRNA, inhibited cell growth in vitro and suppressed xenograft tumor formation in vivo, whereas overexpression of BMX in the cell line C-33A significantly increased cell proliferation. Furthermore, a mechanism study showed that silencing BMX blocked cell cycle transit from G0/G1 to S or G2/M phase, and knockdown of BMX inhibited the expression of p-AKT and p-STAT3. These results suggested that BMX can promote cell proliferation through PI3K/AKT/mTOR and STAT3 signaling pathways in cervical cancer cells.

| S-EPMC5564764 | biostudies-literature

Preconditioning-Activated AKT Controls Neuronal Tolerance to Ischemia through the MDM2-p53 Pathway.

Project description:One of the most important mechanisms of preconditioning-mediated neuroprotection is the attenuation of cell apoptosis, inducing brain tolerance after a subsequent injurious ischemia. In this context, the antiapoptotic PI3K/AKT signaling pathway plays a key role by regulating cell differentiation and survival. Active AKT is known to increase the expression of murine double minute-2 (MDM2), an E3-ubiquitin ligase that destabilizes p53 to promote the survival of cancer cells. In neurons, we recently showed that the MDM2-p53 interaction is potentiated by pharmacological preconditioning, based on subtoxic stimulation of NMDA glutamate receptor, which prevents ischemia-induced neuronal apoptosis. However, whether this mechanism contributes to the neuronal tolerance during ischemic preconditioning (IPC) is unknown. Here, we show that IPC induced PI3K-mediated phosphorylation of AKT at Ser473, which in turn phosphorylated MDM2 at Ser166. This phosphorylation triggered the nuclear stabilization of MDM2, leading to p53 destabilization, thus preventing neuronal apoptosis upon an ischemic insult. Inhibition of the PI3K/AKT pathway with wortmannin or by AKT silencing induced the accumulation of cytosolic MDM2, abrogating IPC-induced neuroprotection. Thus, IPC enhances the activation of PI3K/AKT signaling pathway and promotes neuronal tolerance by controlling the MDM2-p53 interaction. Our findings provide a new mechanistic pathway involved in IPC-induced neuroprotection via modulation of AKT signaling, suggesting that AKT is a potential therapeutic target against ischemic injury.

| S-EPMC8304232 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data