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Diethyl maleate inhibits MCA+TPA transformed cell growth via modulation of GSH, MAPK, and cancer pathways

ABSTRACT: Murine or human cancer cells have high glutathione levels. Depletion of the elevated GSH inhibits proliferation of cancer cells. Molecular basis for this observation is little understood. In an attempt to find out the underlying mechanism, we reproduced these effects in transformed C3H10T1/2 and BALB/c 3T3 cells using diethyl maleate and studied cytogenomic changes in the whole mouse genome using spotted 8 × 60K arrays. Transformed cells revealed an increase in GSH levels. GSH depletion by DEM inhibited the growth of transformed cells. The non-cytotoxic dose of DEM (0.25 mM) resulted in GSH depletion, ROS generation, cell cycle arrest, apoptosis, decrease in anchorage independent growth, gene expression changes and activation of all three members of the MAPK family. Increase in intracellular GSH levels by GSHe countered the effect of DEM. These results support the physiological importance of GSH in regulation of gene expression for transformed cell growth restraint. This study is of interest in not only understanding the molecular biology of the transformed cells, but also in identifying new targets for development of gene therapy together with the chemotherapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE44650 | GEO | 2014/06/02

SECONDARY ACCESSION(S): PRJNA190691

REPOSITORIES: GEO

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Diethyl maleate inhibits MCA+TPA transformed cell growth via modulation of GSH, MAPK, and cancer pathways

Project description:Murine or human cancer cells have high glutathione levels. Depletion of the elevated GSH inhibits proliferation of cancer cells. Molecular basis for this observation is little understood. In an attempt to find out the underlying mechanism, we reproduced these effects in transformed C3H10T1/2 and BALB/c 3T3 cells using diethyl maleate and studied cytogenomic changes in the whole mouse genome using spotted 8 M-CM-^W 60K arrays. Transformed cells revealed an increase in GSH levels. GSH depletion by DEM inhibited the growth of transformed cells. The non-cytotoxic dose of DEM (0.25 mM) resulted in GSH depletion, ROS generation, cell cycle arrest, apoptosis, decrease in anchorage independent growth, gene expression changes and activation of all three members of the MAPK family. Increase in intracellular GSH levels by GSHe countered the effect of DEM. These results support the physiological importance of GSH in regulation of gene expression for transformed cell growth restraint. This study is of interest in not only understanding the molecular biology of the transformed cells, but also in identifying new targets for development of gene therapy together with the chemotherapy. Agilent one-color experiment; Organism: Mus musculus; Agilent Custom Mouse Whole Genome Mouse 8x60k gene expression designed by Genotypic Technology Private Limited; Labeling kit: Agilent Quick-Amp labeling Kit (p/n5190-0442).

2014-06-02 | E-GEOD-44650 | biostudies-arrayexpress

Mus musculus

Project description:Diethyl maleate inhibits MCA+TPA transformed cell growth via modulation of GSH, MAPK, and cancer pathways

| PRJNA190691 | ENA

The effect of insecticide synergist treatment on genome-wide gene expression in a polyphagous pest

Project description:Synergists can counteract metabolic insecticide resistance by inhibiting detoxification enzymes or transporters. In this study we used Illumina RNA-sequencing to investigate genome-wide transcriptional responses in an acaricide resistant strain (JP-R) of the spider mite Tetranychus urticae upon exposure to synergists such as S,S,S-tributyl phosphorotrithioate (DEF), diethyl maleate (DEM), piperonyl butoxide (PBO) and cyclosporin A (CsA).

2017-10-02 | GSE98293 | GEO

Mus musculus

Project description:Expression data in Hepa1c1c7 cells treated with Nrf2 activator, diethyl maleate (DEM)

| PRJNA167691 | ENA

Quantitative phosphoproteomics to unravel the cellular response to chemical stressors with different modes of action

Project description:Cells activate various stress response pathways when exposed to chemicals that can damage cellular macromolecules and organelles. Whether different chemical stressors activate common and/or stressor-specific pathways and to what extent is largely unclear. Here, we used quantitative phosphoproteomics to compare the phosphorylation signaling cascades induced by four stressors with different modes of action: the DNA damaging agent: cisplatin (CDDP), the topoisomerase II inhibitor: etoposide (ETO), the pro-oxidant: diethyl maleate (DEM) and the immunosuppressant: cyclosporine A (CsA). We show that equitoxic doses of these stressors induce distinctive and complex phosphorylation signaling cascades. Our results reveal stressor-specific kinase motifs and pathways. CDDP activates the DNA damage response (DDR) predominantly through the replication-stress related Atr kinase, whereas ETO triggers the DDR through Atr as well as the DNA double stranded break associated Atm kinase. CsA shares with ETO, a strong activation of CK2 kinase and significant Atm phosphorylation but lacks prominent activation of the DDR. Congruent with their known modes of action, CsA-mediated signaling is related to down-regulation of pathways that control hematopoietic differentiation and immunity whereas oxidative stress is the most prominent initiator of DEM-modulated stress signaling. This study presents an unprecedented molecular insight into the activated phosphorylation signaling cascades after various types of stressors.

2020-03-23 | PXD012559 | Pride

Global Gene expression profile of Phorone exposed to Chemically Transformed C3H10T1/2 cells.

Project description:In this study, we have investigated the changes in transformed cells that occur after GSH depletion and may be critical to accentuate the attenuation of carcinogenesis. The in vitro carcinogenesis method and GSH depletor Phorone (PHO) were used. We found that exposure of transformed C3H10T1/2 cells to PHO (2mM) caused attenuation of transformed cell growth as seen in soft agar assay. Loss of cellular GSH content, increase in intracellular ROS generation, and DNA strand break formation also occurred. A microarray based study using 8x60k oligonucleotide array in duplicate revealed changes in global gene expression profile. Our study has identified changes in expression of many genes that may contribute in abatement of carcinogenesis.

2016-04-30 | GSE46469 | GEO

Danio rerio

Project description:Zebrafish embryo response to Diethyl maleate

| PRJNA147331 | ENA

Bevacizumab and Cediranib Maleate in Treating Patients With Metastatic or Unresectable Solid Tumor, Lymphoma, Intracranial Glioblastoma, Gliosarcoma or Anaplastic Astrocytoma

Project description:This phase I trial is studying the side effects and best dose of bevacizumab and cediranib maleate in treating patients with metastatic or unresectable solid tumor, lymphoma, intracranial glioblastoma, gliosarcoma or anaplastic astrocytoma. Monoclonal antibodies, such as bevacizumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Cediranib maleate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Bevacizumab and cediranib maleate may also stop the growth of cancer cells by blocking blood flow to the cancer. Giving bevacizumab together with cediranib maleate may kill more cancer cells.

| 2038889 | ecrin-mdr-crc

Homo sapiens

Project description:MicroRNA levels in non-transformed and transformed lung cells

| PRJNA240886 | ENA

Proteome glioma cell lines LC-MS/MS

Project description:Mutations in isocitrate dehydrogenase 1 or 2 (IDH1/2) define glioma subtypes and are 38 considered primary events in gliomagenesis, impacting tumor epigenetics and metabolism. 39 IDH enzymes are crucial for the generation of reducing potential, yet the impact of the mutation 40 on the cellular antioxidant system is not understood. Here, we investigate how glutathione 41 (GSH) levels are maintained in IDH1 mutant gliomas, despite an altered NADPH/NADP 42 balance. We find that IDH1 mutant astrocytomas specifically upregulate cystathionine γ-lyase 43 (CSE), the enzyme responsible for cysteine production upstream of GSH biosynthesis. Genetic 44 and chemical interference with CSE in patient-derived glioma cells carrying the endogenous 45 IDH1 mutation, sensitized tumor cells to cysteine depletion, an effect not observed in IDH1 46 wild-type gliomas. This correlated with reduced GSH synthesis as shown by in vitro and in vivo 47 serine tracing and led to delayed tumor growth in mice. Thus we show that IDH1 mutant 48 astrocytic gliomas critically rely on NADPH-independent de novo GSH synthesis to maintain 49 the antioxidant defense, which uncovers a novel metabolic vulnerability in this dismal disease.

2021-11-25 | PXD022752 | Pride

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