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The epithelial cell transcriptome after alpha-toxin treatment

ABSTRACT: Responsiveness of cells to alpha-toxin (Hla) from Staphylococcus aureus appears to occur in a cell-type dependent manner. Here, we compare two human bronchial epithelial cell lines, i.e. Hla-susceptible 16HBE14o- and Hla-resistant S9 cells, by a quantitative multi-omics strategy for a better understanding of Hla-induced cellular programs. Phosphoproteomics revealed a substantial impact on phosphorylation-dependent signaling in both cell models and highlights alterations in signaling pathways associated with cell-cell and cell-matrix contacts as well as the actin cytoskeleton as key features of early rHla-induced effects. Along comparable changes in down-stream activity of major protein kinases significant differences between both models were found upon rHla-treatment including activation of EGFR and MAPK1/3 signaling in S9 and repression in 16HBE14o- cells. System-wide transcript and protein expression profiling indicate induction of an immediate early response in either model. In addition, EGFR and MAPK1/3-mediated changes in gene expression suggest cellular recovery and survival in S9 cells but cell death in 16HBE14o- cells. Strikingly, inhibition of the EGFR sensitized S9 cells to Hla indicating that the cellular capacity of activation of the EGFR is a major protective determinant against Hla-mediated cytotoxic effects. Design includes two different human bronchial epithelial cell lines, one control treatment (mock treatment for 2 hours) and one condition (2 alpha toxin treatment for 2 hours). Experiments for both cell line were replicated twice (biological replication).

ORGANISM(S): Homo sapiens

SUBMITTER: Joerg Mostertz

PROVIDER: E-GEOD-65018 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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The epithelial cell transcriptome after alpha-toxin treatment

Project description:Responsiveness of cells to alpha-toxin (Hla) from Staphylococcus aureus appears to occur in a cell-type dependent manner. Here, we compare two human bronchial epithelial cell lines, i.e. Hla-susceptible 16HBE14o- and Hla-resistant S9 cells, by a quantitative multi-omics strategy for a better understanding of Hla-induced cellular programs. Phosphoproteomics revealed a substantial impact on phosphorylation-dependent signaling in both cell models and highlights alterations in signaling pathways associated with cell-cell and cell-matrix contacts as well as the actin cytoskeleton as key features of early rHla-induced effects. Along comparable changes in down-stream activity of major protein kinases significant differences between both models were found upon rHla-treatment including activation of EGFR and MAPK1/3 signaling in S9 and repression in 16HBE14o- cells. System-wide transcript and protein expression profiling indicate induction of an immediate early response in either model. In addition, EGFR and MAPK1/3-mediated changes in gene expression suggest cellular recovery and survival in S9 cells but cell death in 16HBE14o- cells. Strikingly, inhibition of the EGFR sensitized S9 cells to Hla indicating that the cellular capacity of activation of the EGFR is a major protective determinant against Hla-mediated cytotoxic effects.

2015-03-31 | GSE65018 | GEO

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Major determinants of airway epithelial cell sensitivity to S. aureus alpha-toxin: Disposition of toxin heptamers by extracellular vesicle formation and lysosomal degradation

Project description:Alpha-toxin is a major virulence factor of Staphylococcus aureus and plays an important role in S. aureus-induced pneumonia. Different sensitivities toward the toxin of various host cell types have been observed. In this study we investigated internalization of pore-containing areas of the plasma membrane in these cell types as well as potential pathways for heptamer degradation (lysosomal, proteasomal) or disposal (formation of exosomes/microvesicles containing toxin pores). Comparisons of heptamer degradation rates under inhibition of lysosomal or proteasomal degradation revealed that an important route of heptamer degradation at least in S9 cells seemed to be the lysosomal pathway while proteasomal degradation did not seem to be relevant. Exosomes prepared from culture supernatants of toxin-exposed S9 cells, contained alpha-toxin as well as low amounts of marker proteins of exosomes and microvesicles. These results indicate that the ability of lysosomal degradation of internalized toxin heptamers may be the most important determinant of toxin-resistance of some types of airway epithelial cells. In this study, we compared the proteomes of rHla treated (90 min), 8 h starvation and, 48 h starvation for the S9 cells by mass spectrometry.

2021-04-20 | PXD023678 | Pride

Reactivation of ERK signaling causes resistance to EGFR kinase inhibitors (SNP array)

Project description:The clinical efficacy of EGFR kinase inhibitors is limited by the development of drug resistance. The irreversible EGFR kinase inhibitor WZ4002 is effective against the most common mechanism of drug resistance mediated by the EGFR T790M mutation. Here we show that in multiple complementary models harboring EGFR T790M, resistance to WZ4002 develops through aberrant activation of ERK signaling caused by either an amplification of MAPK1 or by downregulation of negative regulators of ERK signaling. Inhibition of MEK or ERK restores sensitivity to WZ4002, and the combination of WZ4002 and a MEK inhibitor prevents the emergence of drug resistance. The WZ4002 resistant MAPK1 amplified cells also demonstrate an increase both in EGFR internalization and a decrease in sensitivity to cytotoxic chemotherapy compared to the parental counterparts. Our findings provide insights into mechanisms of drug resistance to EGFR kinase inhibitors and highlight rational combination therapies that should be evaluated in clinical trials. The EGFR mutant non-small cell lung cancer (NSCLC) cell line PC9 GR4 (delE746_A750/T790M) was exposed to increasing concentrations of WZ4002 similar to previously described methods. Individual clones from WZ4002-resistant (WZR) cells were isolated and confirmed to be drug resistant. Number of samples: 5. PC9GR4 as a control. 4 clones of WZ4002-resistant PC9GR4.

2012-10-01 | E-GEOD-37698 | biostudies-arrayexpress

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2010-06-09 | E-GEOD-1276 | biostudies-arrayexpress

Aberrant ERK signaling causes resistance to EGFR kinase inhibitors

Project description:The clinical efficacy of EGFR kinase inhibitors is limited by the development of drug resistance. The irreversible EGFR kinase inhibitor WZ4002 is effective against the most common mechanism of drug resistance mediated by the EGFR T790M mutation. Here we show that in multiple complementary models harboring EGFR T790M, resistance to WZ4002 develops through aberrant activation of ERK signaling caused by either an amplification of MAPK1 or by downregulation of negative regulators of ERK signaling. Inhibition of MEK or ERK restores sensitivity to WZ4002, and the combination of WZ4002 and a MEK inhibitor prevents the emergence of drug resistance. The WZ4002 resistant MAPK1 amplified cells also demonstrate an increase both in EGFR internalization and a decrease in sensitivity to cytotoxic chemotherapy compared to the parental counterparts. Our findings provide insights into mechanisms of drug resistance to EGFR kinase inhibitors and highlight rational combination therapies that should be evaluated in clinical trials. Our study identifies ERK signaling as a mediator of resistance to irreversible pyrimidine EGFR inhibitors in EGFR T790M-bearing cancers. We further provide a therapeutic strategy to both treat and prevent the emergence of this resistance mechanism. To generate drug-resistant NCI-H1975 cell lines, non-small cell lung cancer (NSCLC) cells were exposed to increasing concentrations of WZ4002 similar to previously described methods. Individual clones from WZ4002-resistant (WZR) cells were isolated and confirmed to be drug resistant. Clone #6, designated as WZR6, was used in this study. For expression analysis, samples were prepared in triplicate from parental NCI-H1975 and NCI-H1975 WZR6 cells.

2012-10-01 | E-GEOD-37699 | biostudies-arrayexpress

Reactivation of ERK signaling causes resistance to EGFR kinase inhibitors (SNP array)

2012-10-01 | GSE37698 | GEO

Aberrant ERK signaling causes resistance to EGFR kinase inhibitors

Project description:The clinical efficacy of EGFR kinase inhibitors is limited by the development of drug resistance. The irreversible EGFR kinase inhibitor WZ4002 is effective against the most common mechanism of drug resistance mediated by the EGFR T790M mutation. Here we show that in multiple complementary models harboring EGFR T790M, resistance to WZ4002 develops through aberrant activation of ERK signaling caused by either an amplification of MAPK1 or by downregulation of negative regulators of ERK signaling. Inhibition of MEK or ERK restores sensitivity to WZ4002, and the combination of WZ4002 and a MEK inhibitor prevents the emergence of drug resistance. The WZ4002 resistant MAPK1 amplified cells also demonstrate an increase both in EGFR internalization and a decrease in sensitivity to cytotoxic chemotherapy compared to the parental counterparts. Our findings provide insights into mechanisms of drug resistance to EGFR kinase inhibitors and highlight rational combination therapies that should be evaluated in clinical trials. Our study identifies ERK signaling as a mediator of resistance to irreversible pyrimidine EGFR inhibitors in EGFR T790M-bearing cancers. We further provide a therapeutic strategy to both treat and prevent the emergence of this resistance mechanism.

2012-10-01 | GSE37699 | GEO

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2012-05-31 | E-GEOD-37588 | biostudies-arrayexpress

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