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RNA-seq analysis revealed that lapatinib-induced keratinocyte apoptosis is related to mitochondrial dysfunction and DNA damage

ABSTRACT: RNA-seq analysis revealed that lapatinib-induced keratinocyte apoptosis is related to mitochondrial dysfunction and DNA damage

PROVIDER: PRJNA801876 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17818830_1.fastq.gz	Fastqsanger.gz
	SRR17818830_2.fastq.gz	Fastqsanger.gz
	SRR17818831_1.fastq.gz	Fastqsanger.gz
	SRR17818831_2.fastq.gz	Fastqsanger.gz
	SRR17818832_1.fastq.gz	Fastqsanger.gz

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RNA-seq analysis revealed that lapatinib-induced keratinocyte apoptosis is related to mitochondrial dysfunction and DNA damage

Project description:Lapatinib, a widely used dual EGFR and ERBB2 inhibitor, have been seriously limited due to skin rash, one of its most common adverse effects caused by EGFR inhibitors in clinical. Here, we found that lapatinib could induce mitochondrial dysfunction, lead to DNA damage and finally cause apoptosis of keratinocytes according to the RNA-sequencing clues. Mechanistically, downregulated expression of DNA repair protein HMGB1 played a critical role in these toxic reaction processes. We found that saikosaponin A could significantly rescue the reduced HMGB1 transcription, which could alleviate lapatinib-induced DNA damage, inhibit keratinocyte apoptosis and further prevent the cutaneous toxicity in mice caused by lapatinib.

2022-12-01 | GSE195713 | GEO

Lapatinib antitumor effect is associated with PI3K and MAPK pathway: an analysis in human and canine prostate cancer cells

Project description:The aberrant activation of HER2 has a pivotal role in bone metastasis implantation and progression in several tumor types, in-cluding prostate cancer (PC). Trastuzumab and other anti-HER2 therapies, such as lapatinib, have been used in human breast cancer HER2 positive. Although HER2 overexpression has been reported in PC, anti-HER2 therapy response has revealed conflicting results. We investigated the potential of lapatinib in inhibiting cell migration and inducing apoptosis in two human (LNCaP and PC3) and two canine PC cell lines (PC1 and PC2). Cell migration and apoptosis were evaluated by Annexin V/PI analysis after lapatinib treatment. The transcriptome analysis of all cell lines before and after treatment with lapatinib was also performed. We found increased apoptosis and migration inhibition in LNCaP cells (androgen-sensitive cell line), while PC1, PC2, and PC3 cells showed no alterations after the treatment. The transcriptome analysis of LNCaP and PC3 cell lines showed 158 dysregulated transcripts in common, while PC1 and PC2 cell lines presented 82. At the doses of lapatinib used, we observed transcriptional modifications in all cell lines. PI3K/AKT/mTOR pathway were enriched in human PC cells, while canine PC cells showed en-richment of tyrosine kinase antitumor response and HER2-related pathways. In canine PC cells, the apoptosis failed after lapatinib treatment, possibly due to the downregulation of MAPK genes. Prostate cancer cells insensitive to androgens may be resistant to lapatinib through PI3K gene dysregulation. The association of lapatinib with PI3K inhibitors may provide a more effective anti-tumor response and clinical benefits to PC patients.

2023-11-30 | E-MTAB-13551 | biostudies-arrayexpress

Lapatinib antitumor effect is associated with PI3K and MAPK pathway: an analysis in human and canine prostate cancer cells

2023-11-30 | E-MTAB-13552 | biostudies-arrayexpress

Acquired resistance to lapatinib

Project description:These studies are aimed at understanding gene expression chnages in a Her2 positive breast cancer cell line that has developed acquired resistance to lapatinib. Samples include SKBR3 parental and resistant (SKBR3-R) under basal conditions and in response to 0.1 and 1uM lapatinib treatment after 24 hours.

2012-06-30 | GSE38376 | GEO

Lapatinib-Induced Enhancement Of Mitochondrial Respiration In HER2-Positive SK-BR-3 Cells: Mechanism Revealed By Analysis Of Proteomic But Not Transcriptomic Data

Project description:Dual inhibitors of HER2 and EGFR, such as lapatinib, have shown significant efficacy for the therapy of HER2-positive breast cancer. Previous experiments showed that in cell cultures, the efficacy of lapatinib was significantly reduced by exposure to human serum and human epidermal growth factor (EGF). At the proteomic and transcriptomic levels, we examined the changes in the HER2-positive breast cancer cell line SK-BR-3 profiles upon treatment with lapatinib, either alone or in combination with human serum or EGF. Proteomic profiling revealed 350 differentially expressed proteins (DEPs) in response to lapatinib treatment at concentrations that induced cell growth arrest. Addition of human serum or EGF in combination with lapatinib prevented cell growth inhibition, and this combination treatment returned the expression of ~93% of DEPs to drug-free levels for both human serum and EGF. Gene ontology enrichment and OncoboxPD pathway activation level analysis showed that lapatinib addition influenced mostly common functional processes revealed in RNA- and protein-based assays. However, a specific feature was observed at the proteome level: addition of lapatinib increased the expression of proteins associated with mitochondrial function and cellular respiration. This feature was not observed when using RNA sequencing data for the same experiments. However, it is consistent with the results of the resazurin test, which showed a 1.8-fold increase in SK-BR-3 cellular respiration upon exposure to lapatinib. Thus, we conclude that enhanced cellular respiration is a novel additional mechanism of action of lapatinib on HER2-positive cancer cells.

2024-09-26 | PXD054180 | Pride

Human breast cancer cells: parental v.s lapatinib-resistant clone

Project description:Transcriptional profiling of human HER2-positive BT474 breast cancer cells comparing control untreated cancer cells with lapatinib-resistant clone established by chronic treatment with lapatinib

2013-10-31 | GSE51889 | GEO

PP2Ac knockdown attenuates lipotoxicity-induced pancreatic β-cell dysfunction and apoptosis

Project description:PP2Ac knockdown attenuates lipotoxicity-induced pancreatic β-cell dysfunction and apoptosis

| PRJNA1013896 | ENA

Human breast cancer cells: parental v.s lapatinib-resistant clone

2013-10-31 | E-GEOD-51889 | biostudies-arrayexpress

Mitochondrial dysfunction caused by bacterial outer membranes vesicles activates intrinsic apoptosis and inflammation

Project description:Sensing of microbes activates the immune system, depending on functional mitochondria. However, pathogenic bacteria inhibit mitochondria activity by delivering toxins via outer membrane vesicles (OMVs). How innate immune cells respond to pathogenic microbes that target mitochondria remains unclear. Here, we show that macrophages induce mitochondrial apoptosis and the NLRP3 inflammasome in response OMVs. Macrophages treated with OMVs and toxins that cause mitochondria dysfunction cease host protein translation which depletes pro-survival BCL-2 family member, MCL-1, and induces BAK-dependent mitochondrial apoptosis. Mitochondrial apoptosis and potassium ion efflux activate the NLRP3 inflammasome after OMV exposure. Importantly, mitochondrial apoptosis modulates IL-1 serum levels in response to OMVs. Our data highlight how innate immune cells sense infections by monitoring mitochondrial health.

2020-07-30 | PXD018563 | Pride

SKBR3/HER2+ Breast Cancer Cellular Response to Lapatinib and Ipatasertib Kinase Inhibitors

Project description:To explore the broader impact of kinase inhibitors on breast cancer cells, SKBR3/HER2+ cells were treated with two small molecule drugs, i.e., Lapatinib (10 uM) - a Tyr kinase inhibitor, and Ipatasertib (1 uM) - a Ser/Thr kinase inhibitor. Serum-starved cells (24 h) were exposed for 36 h to Lapatinib/EGF or a combination of Lapatinib/Ipatasertib/EGF. EGF - only stimulated cells were used as control. The EGF concentration was 10 nM throughout all experiments. Proteomic profiles of nuclear and cytoplasmic cell fractions of treated vs non-treated cells were generated by nano-LC-MS/MS using an Orbitrap QE instrument.

2024-08-23 | PXD051094 | Pride