Browse
Submit Data
Databases
API
Help

Dataset Information

33 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Lobaplatin-Induced Apoptosis Requires p53-Mediated p38MAPK Activation Through ROS Generation in Non-Small-Cell Lung Cancer.

ABSTRACT: Platinum-based chemotherapy is recommended as the first-line treatment regimen for patients with advanced non-small-cell lung cancer (NSCLC). Lobaplatin (LBP), a third-generation platinum anti-neoplastic agent, has shown an improved efficacy. This study is aimed to investigate the mechanisms of LBP-induced apoptosis in the A549 p53 wild-type cell line. The Cell Counting Kit-8 assay (CCK-8), flow cytometry (FCM), Western blot, xenograft tumor models, terminal deoxynucleotide transferase dUTP nick end labeling (TUNEL), and RNA interference were used in this study. Our results showed that the proliferation of A549 cells could be inhibited by LBP. At lower concentrations, LBP triggered cell cycle arrest at the G1 phase in A549 cells. LBP could also induce apoptosis of A549 cells. LBP also increased the expression of PARP and Bax and the cleavage of caspase-3, caspase-8, and caspase-9 and reduced Bcl-2 expression. In vivo experiment confirmed that LBP could inhibit tumor growth in the A549 xenograft models and induce apoptosis. Apoptosis of A549 cells was decreased after transfected with p53 shRNA or treated with reactive oxygen species inhibitor NAC and p38MAPK inhibitor SB203580, suggesting that the p53/ROS/p38MAPK pathway appeared to mediate the LBP-induced apoptosis of A549 cells. Our data demonstrate that LBP could be a promising candidate for the treatment of NSCLC with wild-type p53.

SUBMITTER: Zhang H

PROVIDER: S-EPMC6689983 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Artocarpin, an isoprenyl flavonoid, induces p53-dependent or independent apoptosis via ROS-mediated MAPKs and Akt activation in non-small cell lung cancer cells.

Project description:Artocarpin has been shown to exhibit cytotoxic effects on different cancer cells, including non-small cell lung carcinoma (NSCLC, A549). However, the underlying mechanisms remain unclear. Here, we explore both p53-dependent and independent apoptosis pathways in artocarpin-treated NSCLC cells. Our results showed that artocarpin rapidly induced activation of cellular protein kinases including Erk1/2, p38 and AktS473. Inhibition of these protein kinases prevented artocarpin-induced cell death. Moreover, artocarpin-induced phosphorylation of these protein kinases and apoptosis were mediated by induction of reactive oxygen species (ROS), as pretreatment with NAC (a ROS scavenger) and Apocynin (a Nox-2 inhibitor) blocked these events. Similarly, transient transfection of p47Phox or p91Phox siRNA attenuated artocarpin-induced NADPH oxidase activity and cell death. In addition, p53 dependent apoptotic proteins including PUMA, cytochrome c, Apaf-1 and caspase 3 were activated by artocarpin, and these effects can be abolished by antioxidants, MAPK inhibitors (U0126 and SB202190), but not by PI3K inhibitor (LY294002). Furthermore, we found that artocarpin-induced Akt phosphorylation led to increased NF-?B activity, which may act as an upstream regulator in the c-Myc and Noxa pathway. Therefore, we propose that enhancement of both ERK/ p38/ p53-dependent or independent AktS473/NF-?B/c-Myc/Noxa cascade by Nox-derived ROS generation plays an important role in artocarpin-induced apoptosis in NSCLC cells.

| S-EPMC5438654 | biostudies-literature

Berberine induces non-small cell lung cancer apoptosis via the activation of the ROS/ASK1/JNK pathway.

Project description:BackgroundNon-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers. Berberine (BBR), an isoquinoline alkaloid, is commonly used in traditional Chinese medicine. Previous studies have shown that BBR has a potential anti-tumor effect. However, the mechanisms of BBR on mitochondrial function in anti-lung cancer remain unknown. The aim of this study was to explore mitochondrial function in anti-tumor mechanisms of BBR in NSCLC.MethodsThe NSCLCs were cultured and treated with various doses (40, 80, 120 µg/mL) of BBR for 24 and 48 h. Cell viability was evaluated using Cell Counting Kit-8 (CCK-8). Cell apoptosis, reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were detected by flow cytometry. Relative protein expression was examined by western blot and immunohistochemical (IHC) analysis.ResultsBBR potently suppressed NSCLC cells growth by inducing apoptosis in a dose-and time-dependent manner. BBR induced apoptosis in NSCLC cells as evidenced by caspase-3 cleavage, cytochrome c release, and mitochondrial membrane depolarization. BBR-induced, dose-dependent induction of apoptosis was accompanied by sustained phosphorylation of c-jun-NH2-kinase (JNK) and the JNK inhibitor (SP600125) significantly suppressed BBR-induced apoptosis, N-acetyl cysteine (NAC), a ROS scavenger, was sufficient to both suppress apoptosis signal-regulating kinase 1 (ASK1) and JNK activation and disrupt apoptotic induction.ConclusionsThe results suggest that BBR induces apoptosis of NSCLC cells via ROS-mediated ASK1/JNK activation and the mitochondrial pathway.

| S-EPMC9096398 | biostudies-literature

BMP9-Induced Survival Effect in Liver Tumor Cells Requires p38MAPK Activation.

Project description:The study of bone morphogenetic proteins (BMPs) role in tumorigenic processes, and specifically in the liver, has gathered importance in the last few years. Previous studies have shown that BMP9 is overexpressed in about 40% of hepatocellular carcinoma (HCC) patients. In vitro data have also shown evidence that BMP9 has a pro-tumorigenic action, not only by inducing epithelial to mesenchymal transition (EMT) and migration, but also by promoting proliferation and survival in liver cancer cells. However, the precise mechanisms driving these effects have not yet been established. In the present work, we deepened our studies into the intracellular mechanisms implicated in the BMP9 proliferative and pro-survival effect on liver tumor cells. In HepG2 cells, BMP9 induces both Smad and non-Smad signaling cascades, specifically PI3K/AKT and p38MAPK. However, only the p38MAPK pathway contributes to the BMP9 growth-promoting effect on these cells. Using genetic and pharmacological approaches, we demonstrate that p38MAPK activation, although dispensable for the BMP9 proliferative activity, is required for the BMP9 protective effect on serum withdrawal-induced apoptosis. These findings contribute to a better understanding of the signaling pathways involved in the BMP9 pro-tumorigenic role in liver tumor cells.

| S-EPMC4613212 | biostudies-literature

PERK/eIF-2α/CHOP Pathway Dependent ROS Generation Mediates Butein-induced Non-small-cell Lung Cancer Apoptosis and G2/M Phase Arrest.

Project description:Butein, a member of the chalcone family, is a potent anticarcinogen against multiple cancers, but its specific anti-NSCLC mechanism remains unknown. The present study examined the effects of butein treatment on NSCLC cell lines and NSCLC xenografts. Butein markedly decreased NSCLC cell viability; inhibited cell adhesion, migration, invasion, and colony forming ability; and induced cell apoptosis and G2/M phase arrest in NSCLC cells. Moreover, butein significantly inhibited PC-9 xenograft growth. Both in vivo and in vitro studies verified that butein exerted anti-NSCLC effect through activating endoplasmic reticulum (ER) stress-dependent reactive oxygen species (ROS) generation. These pro-apoptotic effects were reversed by the use of 4- phenylbutyric acid (4-PBA), CHOP siRNA, N-acetyl-L-cysteine (NAC) and Z-VAD-FMK (z-VAD) in vitro. Moreover, inhibition of ER stress markedly reduced ROS generation. In addition, in vivo studies further confirmed that inhibition of ER stress or oxidative stress partially abolished the butein-induced inhibition of tumor growth. Therefore, butein is a potential therapeutic agent for NSCLC, and its anticarcinogenic action might be mediated by ER stress-dependent ROS generation and the apoptosis pathway.

| S-EPMC6643215 | biostudies-literature

Alkaline ceramidase 2 is a novel direct target of p53 and induces autophagy and apoptosis through ROS generation.

Project description:ACER2 is a critical sphingolipid metabolizing enzyme, and has been shown to be remarkably up-regulated following various stimuli such as DNA damage. However, the transcriptional regulatory mechanism of ACER2 gene and its potential role in the regulation of autophagy remain unknown. In this study, we have for the first time identified the human ACER2 gene promoter, and found that human ACER2 transcription is directly regulated by p53 and ACER2 is implicated in the induction of autophagy as well as apoptosis. A series of luciferase reporter assay demonstrated that ACER2 major promoter is located within its first intron where the consensus p53-binding sites exist. Consistently, forced expression of p53 significantly stimulated ACER2 transcription. Notably, p53-mediated autophagy and apoptosis were markedly enhanced by ACER2. Depletion of the essential autophagy gene ATG5 revealed that ACER2-induced autophagy facilitates its effect on apoptosis. Further studies clearly showed that ACER2-mediated autophagy and apoptosis are accompanied by ROS generation. In summary, our present study strongly suggests that ACER2 plays a pivotal role in p53-induced autophagy and apoptosis, and thus might serve as a novel and attractive molecular target for cancer treatment.

| S-EPMC5353723 | biostudies-literature

Phenethyl Isothiocyanate Induces Apoptosis Through ROS Generation and Caspase-3 Activation in Cervical Cancer Cells.

Project description:The latest research shows that current chemotherapeutics are ineffective because of the development of resistance in cervical cancer cells, and hence, their scope of use is limited. The main concern of researchers at the moment is the discovery of safe and effective antiproliferative plant chemicals that can aid in the battle against cervical cancer. Previous studies have shown the possible anticancer potential of phenethyl isothiocyanate obtained from cruciferous plants for many cancers, which targets various signaling pathways to exercise chemopreventive and therapeutic effects. This provides the basis for studying phenethyl isothiocyanate's therapeutic potential against cervical cancer. In the present study, cervical cancer cells were treated with various doses of phenethyl isothiocyanate, alone and in combination with cisplatin. Phenethyl isothiocyanate alone was sufficient to cause nucleus condensation and fragmentation and induce apoptosis in cervical cancer cells, but evident synergistic effects were observed in combination with cisplatin. In addition, phenethyl isothiocyanate treatment increased the production of intracellular ROS in a dose-dependent manner in cervical cancer cells. Furthermore, investigation of phenethyl isothiocyanate induced mitochondrial reactive oxygen species production, and activation of caspases showed that phenethyl isothiocyanate significantly activated caspase-3.

| S-EPMC8358204 | biostudies-literature

miRNA-214 modulates radiotherapy response of non-small cell lung cancer cells through regulation of p38MAPK, apoptosis and senescence.

Project description:BackgroundRadio- and chemotherapy (RT/CT) resistance hampers success in combating small and non-small cell lung cancers (SCLC/NSCLC). The underlying molecular mechanisms of RT/CT resistance of LCs are multifactorial and have been understood in part hitherto. miRNAs, key regulators of mRNAs, are well-recognised oncomirs; however, their role in regulating RT response remains poorly understood.MethodsSix human NSCLC and five SCLC cell lines with different SF2 values were investigated. Using microarray we examined whether expression of miRNAs is linked to the RT resistance of NSCLCs or SCLCs. Obtained data were validated by quantitative real-time PCR. Apoptosis and senescence were analysed using siRNA transfection, western blot and flow cytometry.ResultsmiRNA-21, miRNA-1827, miRNA-214, miRNA-339-5p, miRNA-625, miRNA-768-3p, miRNA-523-3p, miRNA-1227, miRNA-324-5p, miRNA-423-3p, miRNA-1301 and miRNA-1249 are differentially expressed in LC cells. miRNA-214 is upregulated in RT-resistant NSCLC cells relative to radiosensitive counterparts. Considering miRNA-214 as a putative regulator of RT resistance, we demonstrate that knockdown of miRNA-214 in radioresistant NSCLCs sensitised them to RT by stimulation of senescence. Consistently, overexpression of miRNA-214 in radiosensitive NSCLCs protected against RT-induced apoptosis. Protection was mediated by p38MAPK, as downregulation of this kinase could reverse the miRNA-214 overexpression-induced resistance of NSCLC cells.ConclusionmiRNA profiling of LC revealed putative RT resistance signalling circuits, which might help in sensitisation of LC to RT.

| S-EPMC3494421 | biostudies-literature

Guaiazulene Triggers ROS-Induced Apoptosis and Protective Autophagy in Non-small Cell Lung Cancer.

Project description:Non-small cell lung cancer (NSCLC) is one of the most frequent cancers worldwide, yet effective treatment remains a clinical challenge. Guaiazulene (GYZ), a cosmetic color additive, has previously been characterized as a potential antitumor agent due to observed anticancer effects. However, the efficacy of GYZ in the treatment of NSCLC and the involved molecular mechanisms remain largely unknown. Here, we indicated a role for GYZ in the suppression of NSCLC both in vitro and in vivo via triggering reactive oxygen species (ROS)-induced apoptosis. Concomitantly, GYZ induced complete autophagic flux in NSCLC cells via inhibiting the Akt/mTOR signaling pathway, which displayed cytoprotective effect against GYZ-induced growth suppression. Accompanied with autophagy inhibition obviously enhanced the effects of GYZ. Notably, GYZ acts synergistically with paclitaxel in the suppression of NSCLC in vitro. Together, our results for the first time reported that GYZ suppressed the proliferation of NSCLC and suggested a potential strategy for inhibiting NSCLC growth by combinational use of GYZ and autophagy inhibitors.

| S-EPMC8082441 | biostudies-literature

T cell activation requires force generation.

Project description:Triggering of the T cell receptor (TCR) integrates both binding kinetics and mechanical forces. To understand the contribution of the T cell cytoskeleton to these forces, we triggered T cells using a novel application of atomic force microscopy (AFM). We presented antigenic stimulation using the AFM cantilever while simultaneously imaging with optical microscopy and measuring forces on the cantilever. T cells respond forcefully to antigen after calcium flux. All forces and calcium responses were abrogated upon treatment with an F-actin inhibitor. When we emulated the forces of the T cell using the AFM cantilever, even these actin-inhibited T cells became activated. Purely mechanical stimulation was not sufficient; the exogenous forces had to couple through the TCR. These studies suggest a mechanical-chemical feedback loop in which TCR-triggered T cells generate forceful contacts with antigen-presenting cells to improve access to antigen.

| S-EPMC4896056 | biostudies-literature

Andrographolide induces vascular smooth muscle cell apoptosis through a SHP-1-PP2A-p38MAPK-p53 cascade.

Project description:The abnormal growth of vascular smooth muscle cells (VSMCs) is considered a critical pathogenic process in inflammatory vascular diseases. We have previously demonstrated that protein phosphatase 2 A (PP2A)-mediated NF-κB dephosphorylation contributes to the anti-inflammatory properties of andrographolide, a novel NF-κB inhibitor. In this study, we investigated whether andrographolide causes apoptosis, and characterized its apoptotic mechanisms in rat VSMCs. Andrographolide activated the p38 mitogen-activated protein kinase (p38MAPK), leading to p53 phosphorylation. Phosphorylated p53 subsequently transactivated the expression of Bax, a pro-apoptotic protein. Transfection with pp2a small interfering RNA (siRNA) suppressed andrographolide-induced p38MAPK activation, p53 phosphorylation, and caspase 3 activation. Andrographolide also activated the Src homology 1 domain-containing protein tyrosine phosphatase (SHP-1), and induced PP2A dephosphorylation, both of which were inhibited by the SHP-1 inhibitor sodium stibogluconate (SSG) or shp-1 siRNA. SSG or shp-1 siRNA prevented andrographolide-induced apoptosis. These results suggest that andrographolide activates the PP2A-p38MAPK-p53-Bax cascade, causing mitochondrial dysfunction and VSMC death through an SHP-1-dependent mechanism.

| S-EPMC4090621 | 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