Agrimoniin synergistically works with erlotinib to inhibit the proliferation of pancreatic cancer by remodeling the tumor microenvironment and suppressing lactic acid expression
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ABSTRACT:
PROVIDER: PRJNA1166910 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30832773_1.fastq.gz | Fastqsanger.gz | |||
| SRR30832773_2.fastq.gz | Fastqsanger.gz | |||
| SRR30832774_1.fastq.gz | Fastqsanger.gz | |||
| SRR30832774_2.fastq.gz | Fastqsanger.gz | |||
| SRR30832775_1.fastq.gz | Fastqsanger.gz |
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Project description:Erlotinib, as an EGFR small molecule inhibitor for pancreatic cancer, its efficacy as monotherapy is limited. Combination of erlotinib and gemcitabine has shown improvement in multiple survival indicators. However, drug resistance remains a challenge. Agrimoniin, the main active ingredient in Agrimonia pilosa, has anticancer potential. Whether it can serve as a synergistic or resistance-reversing drug for erlotinib require further research. In this study, we performed subcutaneous xenograft tumor experiments, CCK8, EdU assays, flow cytometry, HE staining, immunohistochemical and western blot to explore the synergistic effects of agrimoniin and erlotinib in inhibiting pancreatic cancer. Single-cell RNA sequencing was used to explore the relationship between their synergistic effects and tumor microenvironment. Through western blot and colorimetric assays for lactic acid, we studied the connection between their synergistic effects and aerobic glycolysis as well as lactic acid expression. By employing signal pathway inhibitors and agonists, we studied the positive feedback regulatory mechanism between relevant signal pathways and lactic acid expression. We found that agrimoniin and erlotinib synergistically inhibits the proliferation and promotes the apoptosis of pancreatic cancer cells. Together, they effectively suppress signal interaction among tumor cells, stromal cells and macrophages within subcutaneous tumors. They synergistically inhibit aerobic glycolysis and lactic acid expression in pancreatic cancer. Notably, we uncover the vicious cycle between the PI3K/AKT//HIF-1α/HK2, MEK/ERK/HIF-1α/HK2 signaling pathways and lactic acid expression. Combination of agrimoniin and erlotinib remodels tumor microenvironment, reprograms aerobic glycolysis, disrupts the positive feedback loop between lactic acid and two signaling pathways, thus synergistically inhibits the proliferation of pancreatic cancer cells.
2025-03-01 | GSE278383 | GEO
Project description:The receptor tyrosine kinase (RTK) EGFR is overexpressed and mutated in NSCLC. These mutations can be targeted by RTK inhibitors (TKIs), such as erlotinib. Chromatin-modifying agents offer a novel therapy approach by sensitizing tumor cells to TKIs. The NSCLC cell lines HCC827 (EGFR mutant, adenocarcinoma), A549 (EGFR wt, adenocarcinoma) and NCI-H460 (EGFR wt, large cell carcinoma) were analyzed by SNP6.0 array. Changes in proliferation were quantified by WST-1 assay, apoptosis by Annexin V/7-AAD flow cytometry and histone marks (acH3, H3K4me1,-2,-3) by immunoblotting. Expectedly, the EGFR wt cell lines A549 and NCI-H460 were insensitive to the growth-inhibiting effect of single-agent erlotinib (IC50 70-100µM), compared to HCC827 (IC50 <0.02μM). Treatment with panobinostat diminished growth to <50% in both EGFR wt and <30% in HCC827 cells. The combination of both drugs significantly reduced proliferation by ≥70% in A549, >95% in HCC827, but not further in NCI-H460. Panobinostat alone induced differentiation and expression of p21WAF1/CIP1 and p53 in all three cell lines, with almost no further increase when combined with erlotinib. In contrast, combination treatment additively decreased pERK, pAKT and pEGFR in A549, and synergistically induced acH3 in both adenocarcinoma lines. Surprisingly, we also saw an induction of H3K4 methylation marks in all three cell lines. In conclusion, panobinostat synergistically sensitized lung adenocarcinoma cells to the antiproliferative effects of erlotinib. Since single-agent erlotinib has only modest clinical effects in adenocarcinoma EGFR wt patients, combination therapy with an HDACi might offer a promising therapy approach to extend this activity. Copy-number analysis of three NSCLC cell lines HCC827, A549 and NCI-H460 (in unicates) was performed according to protocol by Affymetrix Genome-Wide Human SNP-Array 6.0.
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Project description:Background: The receptor tyrosine kinase (RTK) EGFR is overexpressed and mutated in NSCLC. These mutations can be targeted by RTK inhibitors (TKIs) such as erlotinib. Chromatin-modifying agents may offer a novel therapeutic approach by sensitizing tumor cells to TKIs. Methods: The NSCLC cell lines HCC827 (EGFR mutant, adenocarcinoma), A549 (EGFR wt, adenocarcinoma) andNCI-H460 (EGFR wt, large cell carcinoma) were analyzed by SNP6.0 array. Changes in proliferation after panobinostat (LBH-589, PS) and erlotinib treatment were quantified by WST-1 assay and apoptosis by Annexin V/7-AAD flow cytometry. Abundance of target proteins and histone marks (acH3, H3K4me1/2/3) was determined by immunoblotting. Results: As expected, the EGFR wt cell lines A549 and NCI-H460 were quite insensitive to the growth-inhibitory effect of single-agent erlotinib (IC50 70-100 μM), compared to HCC827 (IC50 < 0.02 μM). PS treatment diminished growth to <50 % in both EGFR wt cells, and <30 % in HCC827. The combination of both drugs reduced proliferation by >95 % in HCC827, ≥70 % in A549, but not further in NCI-H460. PS alone induced differentiation and expression of p21WAF1/CIP1 and p53 and decreased CHK1 in all three cell lines, with almost no further effect when combined with erlotinib. In contrast, combination treatment additively decreased pEGFR, pERK, pAKT in A549, and synergistically induced acH3 in both adenocarcinoma lines. Surprisingly, we saw an induction of H3K4 methylation marks after erlotinib treatment in HCC827 (and to a lesser extent in A549) that was even further enhanced by combination with PS. Conclusion: We were able to show that PS synergistically sensitized lung adenocarcinoma cells to the antiproliferative effects of erlotinib. Since single-agent erlotinib has only modest clinical effects in lung adenocarcinoma EGFR wt patients, its combination with an HDACi might offer a promising therapy approach.
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Project description:Analysis of human, adult, dermal fibroblasts following treatment with 100nM or 1 uM of erlotinib, a tryrosine kinase inhibitor (TKI) that targets the epidermal growth factor receptor (EGFR) inhibiting EGFR activation and signaling. Erlotinib is widely used to effectively treat patients with advanced non-small cell lung cancer but treatment with erlotinib and other EGFR TKIs are associated with a painful skin rash. Results identified significantly differentially expressed genes in fibroblasts treated with erlotinib providing insight into how the drug alters the transcriptome in ways that may contribute to the TKI-related rash.
2019-01-01 | GSE106151 | GEO
Project description:The non-small cell lung cancer (NSCLC) cell line HCC827 harbors an activating EGFR mutation (exon 19 deletion) that confers sensitivity to the FDA-approved EGFR inhibitor erlotinib. By applying the ClonTracer barcoding system, we were able to show the presence of pre-existing sub-populations in HCC827 that contribute to erlotinib resistance. Prior studies implicated that MET amplification confers resistance to erlotinib in this cell line. Therefore we examined the effects of the c-Met inhibitor crizotinib on the barcoded HCC827 population when treated either sequentially or simultaneously with both inhibitors. Despite the significant reduction in barcode complexity, the erlotinib/crizotinib combination treatment failed to eradicate all of the resistant clones implying the presence of an erlotinib/crizotinib dual resistant subpopulation. We performed transcriptome profiling (RNA-seq) to elucidate the potential resistance mechanisms of the dual resistant subpopulation in comparison to vehicle-treated or single agent erlotinib-resistant HCC827 cell populations as controls.
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Project description:The non-small cell lung cancer (NSCLC) cell line HCC827 harbors an activating EGFR mutation (exon 19 deletion) that confers sensitivity to the FDA-approved EGFR inhibitor erlotinib. By applying the ClonTracer barcoding system, we were able to show the presence of pre-existing sub-populations in HCC827 that contribute to erlotinib resistance. Prior studies implicated that MET amplification confers resistance to erlotinib in this cell line. Therefore we examined the effects of the c-Met inhibitor crizotinib on the barcoded HCC827 population when treated either sequentially or simultaneously with both inhibitors. Despite the significant reduction in barcode complexity, the erlotinib/crizotinib combination treatment failed to eradicate all of the resistant clones implying the presence of an erlotinib/crizotinib dual resistant subpopulation. We performed transcriptome profiling (RNA-seq) to elucidate the potential resistance mechanisms of the dual resistant subpopulation in comparison to vehicle-treated or single agent erlotinib-resistant HCC827 cell populations as controls. mRNA profiling of the subpopulations of human NSCLC cell line HCC827 that contribute to EGFR inhibitor erlotinib and MET inhibitor crizotinib resistance
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Project description:We used next generation sequencing to analyze the effects of Erlotinib incubation on primary human keratinozytes and fibroblasts. We compared miRNA expression in cell lines more reactive to Erlotinib against cell lines less reactive to Erlotinib
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Project description:To identify the potential mechanisms of enhanced activity of combined inhibition of erlotinib and YF454A, we conducted a microarray analysis on gene expression profiles in PC9 erlotinib cells. We used Affymetrix GeneChip® Human Transcriptome Array 2.0 to detail gene expression after indicated treatments and identified the molecular mechanism during this process to facilitate further studies.
2016-04-16 | GSE80316 | GEO
Project description:Elevated expression and activity of the epidermal growth factor receptor (EGFR)/protein kinase B (Akt) signaling pathway is associated with development, progression and treatment resistance of head and neck cancer (HNC). Several studies have demonstrated that microRNA-7 (miR-7) regulates EGFR expression and Akt activity in a range of cancer cell types via its specific interaction with the EGFR mRNA 3′ untranslated region (3′-UTR). In the present study, we found that miR-7 regulated EGFR expression and Akt activity in HNC cell lines, and that this was associated with reduced growth in vitro and in vivo of cells (HN5) that were sensitive to the EGFR tyrosine kinase inhibitor (TKI) erlotinib (Tarceva). miR-7 acted synergistically with erlotinib to inhibit growth of erlotinib-resistant FaDu cells, an effect associated with increased inhibition of Akt activity. Microarray analysis of HN5 and FaDu cell lines transfected with miR-7 identified a common set of downregulated miR-7 target genes, providing insight into the tumor suppressor function of miR-7. Furthermore, we identified several target miR-7 mRNAs with a putative role in the sensitization of FaDu cells to erlotinib. Together, these data support the coordinate regulation of Akt signaling by miR-7 in HNC cells and suggest the therapeutic potential of miR-7 alone or in combination with EGFR TKIs in this disease. Differential gene expression in head and neck cancer cell lines HN5 and FaDu under conditions of 24 h miR-NC (negative control) vs. miR-7 treatment.
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