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Dihydrochelerythrine Induced Ferroptosis via Glutathione Peroxidase 4 Downregulation in Prostate Cancer Cells
Aihua Xu1, Yang Xie2,3, Ruobing Han4
1Department of Clinical Laboratory, Xinxiang Central Hospital, Xinxiang, P. R. China.
Abstract:
The purpose of this study was to elucidate the role of dihydrochelerythrine (DHC) in prostate cancer and to explore its targets in DU145 and PC3 cells. DHC significantly inhibited the growth of both cell lines. RNA-sequencing analysis revealed that ferroptosis-related genes, including glutathione peroxidase 4 (GPX4) and light chain 3, were significantly downregulated in DHC-treated DU145 cells. Molecular docking studies demonstrated significant interactions between DHC and the GPX4 protein, with a binding energy of -9.01 kcal/mol. Furthermore, GPX4 mRNA expression was significantly upregulated in 497 prostate tumor samples compared to normal tissue in the Cancer Genome Atlas prostate adenocarcinoma dataset. DHC markedly induced ferroptosis in DU145 and PC3 cells by suppressing GPX4 expression, increasing mitochondrial membrane density, and reducing/vanishing mitochondrial cristae, leading to lipid reactive oxygen species production. Treatment with Ferrostatin-1 partially rescued the cell viability reduced by DHC. Collectively, these findings suggest that DHC may be a potential agent for inducing ferroptosis in prostate cancer cells by decreasing GPX4 expression.
Insights
Dihydrochelerythrine (DHC) inhibits prostate cancer cell growth by inducing ferroptosis. This compound targets glutathione peroxidase 4 (GPX4), offering a potential therapeutic strategy for prostate cancer.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Prostate cancer remains a significant health concern with ongoing research for novel therapeutic agents.
- Understanding the molecular mechanisms underlying cancer cell death is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the role of dihydrochelerythrine (DHC) in prostate cancer.
- To identify the molecular targets of DHC in prostate cancer cell lines DU145 and PC3.
Main Methods:
- Cell viability assays were performed on DU145 and PC3 cells treated with DHC.
- RNA-sequencing was employed to analyze gene expression changes in DHC-treated cells.
- Molecular docking studies were conducted to assess the interaction between DHC and GPX4.
- Analysis of GPX4 mRNA expression in The Cancer Genome Atlas (TCGA) prostate cancer dataset.
Main Results:
- DHC significantly inhibited the growth of DU145 and PC3 prostate cancer cells.
- RNA-sequencing revealed downregulation of ferroptosis-related genes, including glutathione peroxidase 4 (GPX4), in DHC-treated cells.
- Molecular docking showed strong binding affinity between DHC and GPX4.
- GPX4 was found to be upregulated in prostate tumors compared to normal tissue.
- DHC induced ferroptosis by suppressing GPX4, altering mitochondrial morphology, and increasing lipid reactive oxygen species production.
- Ferrostatin-1 partially rescued DHC-induced cell death.
Conclusions:
- Dihydrochelerythrine (DHC) effectively inhibits prostate cancer cell proliferation.
- DHC induces ferroptosis in prostate cancer cells, mechanistically linked to the suppression of GPX4 expression.
- DHC represents a potential therapeutic candidate for prostate cancer treatment by targeting ferroptosis pathways.
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