Browse
Submit Data
Databases
API
Help

Dataset Information

17 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Nicotinic-nAChR signaling mediates drug resistance in lung cancer.

ABSTRACT: Lung cancer is the leading cause of cancer death worldwide. Cigarette smoking is the most common risk factor for lung carcinoma; other risks include genetic factors and exposure to radon gas, asbestos, secondhand smoke, and air pollution. Nicotine, the primary addictive constituent of cigarettes, contributes to cancer progression through activation of nicotinic acetylcholine receptors (nAChRs), which are membrane ligand-gated ion channels. Activation of nicotine/nAChR signaling is associated with lung cancer risk and drug resistance. We focused on nAChR pathways activated by nicotine and its downstream signaling involved in regulating apoptotic factors of mitochondria and drug resistance in lung cancer. Increasing evidence suggests that several sirtuins play a critical role in multiple aspects of cancer drug resistance. Thus, understanding the consequences of crosstalk between nicotine/nAChRs and sirtuin signaling pathways in the regulation of drug resistance could be a critical implication for cancer therapy.

SUBMITTER: Cheng WL

PROVIDER: S-EPMC6959074 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Nicotinic-nAChR signaling mediates drug resistance in lung cancer.

Cheng Wan-Li WL Chen Kuan-Yuan KY Lee Kang-Yun KY Feng Po-Hao PH Wu Sheng-Ming SM

Journal of Cancer 20200101 5

Lung cancer is the leading cause of cancer death worldwide. Cigarette smoking is the most common risk factor for lung carcinoma; other risks include genetic factors and exposure to radon gas, asbestos, secondhand smoke, and air pollution. Nicotine, the primary addictive constituent of cigarettes, contributes to cancer progression through activation of nicotinic acetylcholine receptors (nAChRs), which are membrane ligand-gated ion channels. Activation of nicotine/nAChR signaling is associated wit ...[more]

PMID: 31956359

Similar Datasets

Modulation of recombinant, ?2*, ?3* or ?4*-nicotinic acetylcholine receptor (nAChR) function by nAChR ?3 subunits.

Project description:The nicotinic acetylcholine receptor (nAChR) ?3 subunit is thought to serve an accessory role in nAChR subtypes expressed in dopaminergic regions implicated in drug dependence and reward. When ?3 subunits are expressed in excess, they have a dominant-negative effect on function of selected nAChR subtypes. In this study, we show, in Xenopus oocytes expressing ?2, ?3 or ?4 plus either ?2 or ?4 subunits, that in the presumed presence of similar amounts of each nAChR subunit, co-expression with wild-type ?3 subunits generally (except for ?3*-nAChR) lowers amplitudes of agonist-evoked, inward peak currents by 20-50% without having dramatic effects (? 2-fold) on agonist potencies. By contrast, co-expression with mutant ?3(V9'S) subunits generally (except for ?4?2*-nAChR) increases agonist potencies, consistent with an expected gain-of-function effect. This most dramatically demonstrates formation of complexes containing three kinds of subunit. Moreover, for oocytes expressing nAChR containing any ? subunit plus ?4 and ?3(V9'S) subunits, there is spontaneous channel opening sensitive to blockade by the open channel blocker, atropine. Collectively, the results indicate that ?3 subunits integrate into all of the studied receptor assemblies and suggest that natural co-expression with ?3 subunits can influence levels of expression and agonist sensitivities of several nAChR subtypes.

| S-EPMC3569009 | biostudies-literature

Lung Cancer Drug resistance LC-MS/MS

Project description:In depth label free quantitative mass spectrometry based proteomics for identification of potential biomarkers of drug resistance in lung cancer.

2023-03-10 | PXD036996 | Pride

PHLDA1 Mediates Drug Resistance in Receptor Tyrosine Kinase-Driven Cancer.

Project description:Development of resistance causes failure of drugs targeting receptor tyrosine kinase (RTK) networks and represents a critical challenge for precision medicine. Here, we show that PHLDA1 downregulation is critical to acquisition and maintenance of drug resistance in RTK-driven cancer. Using fibroblast growth factor receptor (FGFR) inhibition in endometrial cancer cells, we identify an Akt-driven compensatory mechanism underpinned by downregulation of PHLDA1. We demonstrate broad clinical relevance of our findings, showing that PHLDA1 downregulation also occurs in response to RTK-targeted therapy in breast and renal cancer patients, as well as following trastuzumab treatment in HER2+ breast cancer cells. Crucially, knockdown of PHLDA1 alone was sufficient to confer de novo resistance to RTK inhibitors and induction of PHLDA1 expression re-sensitized drug-resistant cancer cells to targeted therapies, identifying PHLDA1 as a biomarker for drug response and highlighting the potential of PHLDA1 reactivation as a means of circumventing drug resistance.

| S-EPMC5848852 | biostudies-literature

Nicotinic acetylcholine receptor (nAChR) mediated dopamine release in larval Drosophila melanogaster.

Project description:Acetylcholine is an excitatory neurotransmitter in the central nervous system of insects and the nicotinic acetylcholine receptor (nAChR) is a target for neonicotinoid insecticides. Functional insect nAChRs are difficult to express in host cells, and hence difficult to study. In mammals, acetylcholine and nicotine evoke dopamine release, but the extent to which this mechanism is conserved in insects is unknown. In intact larval ventral nerve cords (VNCs), we studied dopamine evoked by acetylcholine, nicotine, or neonicotinoids. Using fast-scan cyclic voltammetry, we confirmed dopamine was measured by its cyclic voltammogram and also by feeding Drosophila the synthesis inhibitor, 3-iodotyrosine, which lowered the evoked dopamine response. Acetylcholine (1.8?pmol) evoked on average 0.43?±?0.04??M dopamine. Dopamine release significantly decreased after incubation with ?-bungarotoxin, demonstrating the release is mediated by nAChR, but atropine, a muscarinic AChR antagonist, had no effect. Nicotine (t1/2?=?71?s) and the neonicotinoids nitenpyram and imidacloprid (t1/2?=?86?s, 121?s respectively) also evoked dopamine release, which lasted longer than acetylcholine-stimulated release (t1/2?=?19?s). Nicotine-stimulated dopamine was significantly lower in the presence of sodium channel blocker, tetrodotoxin, showing that the release is exocytotic. Drosophila that have mutations in the nAChR subunit ?1 or ?2 have significantly lower neonicotinoid-stimulated release but no changes in nicotine-stimulated release. This work demonstrates that nAChR agonists mediate dopamine release in Drosophila larval VNC and that mutations in nAChR subunits affect how insecticides stimulate dopamine release.

| S-EPMC5835409 | biostudies-literature

Functional Human ?7 Nicotinic Acetylcholine Receptor (nAChR) Generated from Escherichia coli.

Project description:Human Cys-loop receptors are important therapeutic targets. High-resolution structures are essential for rational drug design, but only a few are available due to difficulties in obtaining sufficient quantities of protein suitable for structural studies. Although expression of proteins in E. coli offers advantages of high yield, low cost, and fast turnover, this approach has not been thoroughly explored for full-length human Cys-loop receptors because of the conventional wisdom that E. coli lacks the specific chaperones and post-translational modifications potentially required for expression of human Cys-loop receptors. Here we report the successful production of full-length wild type human ?7nAChR from E. coli Chemically induced chaperones promote high expression levels of well-folded proteins. The choice of detergents, lipids, and ligands during purification determines the final protein quality. The purified ?7nAChR not only forms pentamers as imaged by negative-stain electron microscopy, but also retains pharmacological characteristics of native ?7nAChR, including binding to bungarotoxin and positive allosteric modulators specific to ?7nAChR. Moreover, the purified ?7nAChR injected into Xenopus oocytes can be activated by acetylcholine, choline, and nicotine, inhibited by the channel blockers QX-222 and phencyclidine, and potentiated by the ?7nAChR specific modulators PNU-120596 and TQS. The successful generation of functional human ?7nAChR from E. coli opens a new avenue for producing mammalian Cys-loop receptors to facilitate structure-based rational drug design.

| S-EPMC5000075 | biostudies-literature

PHLDA1 mediates drug resistance in receptor tyrosine kinase driven cancer

Project description:Mutations or amplifications of receptor tyrosine kinases (RTKs) are common in many cancers. Given the emergence of small molecule inhibitors specific to RTKs, these signalling cascades are attractive therapeutic targets. However, compensatory and adaptation mechanisms limit the clinical utility of compounds that target nodes in RTK networks. Here we show that PHLDA1 down-regulation is critical to acquisition and maintenance of drug resistance in RTK-driven cancer.

2018-02-19 | GSE81169 | GEO

Hypoxia-induced autophagy mediates cisplatin resistance in lung cancer cells.

Project description:Hypoxia which commonly exists in solid tumors, leads to cancer cells chemoresistance via provoking adaptive responses including autophagy. Therefore, we sought to evaluate the role of autophagy and hypoxia as well as the underlying mechanism in the cisplatin resistance of lung cancer cells. Our study demonstrated that hypoxia significantly protected A549 and SPC-A1 cells from cisplatin-induced cell death in a Hif-1α- and Hif-2α-dependent manner. Moreover, compared with normoxia, cisplatin-induced apoptosis under hypoxia was markedly reduced. However, when autophagy was inhibited by 3-MA or siRNA targeted ATG5, this reduction was effectively attenuated, which means autophagy mediates cisplatin resisitance under hypoxia. In parallel, we showed that hypoxia robustly augmented cisplatin-induced autophagy activation, accompanying by suppressing cisplatin-induced BNIP3 death pathways, which was due to the more efficient autophagic process under hypoxia. Consequently, we proposed that autophagy was a protective mechanism after cisplatin incubation under both normoxia and hypoxia. However, under normoxia, autophagy activation 'was unable to counteract the stress induced by cisplatin, therefore resulting in cell death, whereas under hypoxia, autophagy induction was augmented that solved the cisplatin-induced stress, allowing the cells to survival. In conclusion, augmented induction of autophagy by hypoxia decreased lung cancer cells susceptibility to cisplatin-induced apoptosis.

| S-EPMC4511870 | biostudies-literature

WNT5A-NFAT signaling mediates resistance to apoptosis in pancreatic cancer.

Project description:IntroductionWNT5A belongs to the Wnt family of secreted signaling molecules. Using transcriptional profiling, we previously identified WNT5A as target of the antiapoptotic transcription factor CUX1 and demonstrated high expression levels in pancreatic cancer. However, the impact of WNT5A on drug resistance and the signaling pathways employed by WNT5A remain to be elucidated.ObjectivesThis project aims to decipher the impact of WNT5A on resistance to apoptosis and the signaling pathways employed by WNT5A in pancreatic cancer.MethodsThe impact of WNT5A and its downstream effectors on tumor growth and drug resistance was studied in vitro and in xenograft models in vivo. Tissue microarrays of pancreatic cancer specimens were employed for immunohistochemical studies.ResultsKnockdown of WNT5A results in a significant increase in drug-induced apoptosis. In contrast, overexpression of WNT5A or addition of recombinant WNT5A mediates resistance to apoptosis in vitro. In our attempt to identify downstream effectors of WNT5A, we identified the transcription factor nuclear factor of activated T cells c2 (NFATc2) as transcriptional target of WNT5A signaling. NFATc2 confers a strong antiapoptotic phenotype mediating at least in part the effects of WNT5A on drug resistance and tumor cell survival. In vivo, WNT5A expression leads to resistance to gemcitabine-induced apoptosis in a xenograft model, which is paralleled by up-regulation of NFATc2. Both WNT5A and NFATc2 proteins are highly expressed in human pancreatic cancer tissues and their expression levels correlated significantly.ConclusionWe identified the WNT5A-NFATc2 axis as important mediator of drug resistance in pancreatic cancer.

| S-EPMC3556935 | biostudies-literature

Mitochondrial temperature-responsive drug delivery reverses drug resistance in lung cancer.

Project description:Reversal of cancer drug resistance remains a critical challenge in chemotherapy. Mitochondria-targeted drug delivery has been suggested to mitigate drug resistance in cancer. To overcome the intrinsic limitations in conventional mitochondrial targeting strategies, we develop mitochondrial temperature-responsive drug delivery to reverse doxorubicin (DOX) resistance in lung cancer. Results demonstrate that the thermoresponsive nanocarrier can prevent DOX efflux and facilitate DOX accumulation and mitochondrial targeting in DOX-resistant tumors. As a consequence, thermoresponsive nanocarrier enhances the cytotoxicity of DOX and reverses the drug resistance in tumor-bearing mice. This work represents the first example of mitochondrial temperature-responsive drug delivery for reversing cancer drug resistance.

| S-EPMC8844157 | biostudies-literature

PHLDA1 mediates drug resistance in receptor tyrosine kinase driven cancer

Project description:Development of resistance causes failure of drugs targeting receptor tyrosine kinase (RTK) networks, and represents a critical challenge for precision medicine. Here we show that PHLDA1 down-regulation is critical to acquisition and maintenance of drug resistance in RTK-driven cancer. Using FGFR inhibition in endometrial cancer cells, we identify an Akt-driven compensatory mechanism underpinned by down-regulation of PHLDA1. We demonstrate broad clinical relevance of our findings, showing that PHLDA1 down-regulation also occurs in response to RTK-targeted therapy in breast and renal cancer patients, as well as following trastuzumab treatment in HER2+ breast cancer cells. Crucially, knockdown of PHLDA1 alone was sufficient to confer de novo resistance to RTK inhibitors, and induction of PHLDA1 expression re-sensitised drug resistant cancer cells to targeted therapies, identifying PHLDA1 as a biomarker for drug response and highlighting the potential of PHLDA1 reactivation as a means of circumventing drug resistance.

2018-03-05 | PXD008859 | Pride

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