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Investigating the Molecular Impact of GGMSC on Redox and Metabolic Pathways in Pancreatic Cancer Cells
Arun Kumar Selvam1, Mehran Ghaderi2,3, Joakim Dillner2,3
1Department of Laboratory Medicine, Division of Pathology F46, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden.
Abstract:
Pancreatic ductal adenocarcinoma (PDAC) remains a highly aggressive malignancy with limited treatment options. Targeting metabolic vulnerabilities and disrupting redox stress pathways has gained increasing attention as a potential therapeutic strategy. γ-Glutamyl-selenomethylselenocysteine (GGMSC) is a selenium-containing compound structurally related to seleno-L-methylselenocysteine (MSC), which has shown anticancer potential in preclinical models, although its molecular effects in PDAC are not well defined. In this study, we investigated the transcriptomic response to high-dose GGMSC in two PDAC cell lines, CAPAN-2 and HPAF-II. RNA sequencing and cytotoxicity assays revealed marked sensitivity to GGMSC in CAPAN-2 cells, associated with activation of oxidative stress and ferroptosis-related pathways, alongside downregulation of metabolic and cell cycle genes. Conversely, HPAF-II cells displayed limited transcriptional alterations and maintained proliferative and metabolic programs. These findings offer insights into the molecular mechanisms underlying GGMSC-induced transcriptional responses in PDAC and suggest potential avenues for future investigations of selenium-based therapies in pancreatic cancer.
Insights
γ-Glutamyl-selenomethylselenocysteine (GGMSC) shows promise in treating pancreatic cancer. High-dose GGMSC activated oxidative stress and ferroptosis pathways in sensitive pancreatic ductal adenocarcinoma cells.
Area of Science:
- Oncology
- Biochemistry
- Molecular Biology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with limited therapeutic options.
- Targeting metabolic vulnerabilities and redox stress pathways is a promising strategy for PDAC treatment.
- Selenium compounds, like γ-Glutamyl-selenomethylselenocysteine (GGMSC), show anticancer potential, but their molecular effects in PDAC require further elucidation.
Purpose of the Study:
- To investigate the transcriptomic response to high-dose GGMSC in two distinct PDAC cell lines (CAPAN-2 and HPAF-II).
- To identify the molecular mechanisms underlying GGMSC's effects on PDAC cells.
- To explore the potential of GGMSC as a therapeutic agent for pancreatic cancer.
Main Methods:
- Utilized RNA sequencing to analyze the transcriptomic alterations in PDAC cells treated with GGMSC.
- Performed cytotoxicity assays to assess the sensitivity of PDAC cell lines to GGMSC.
- Compared the molecular responses between GGMSC-sensitive (CAPAN-2) and GGMSC-resistant (HPAF-II) cell lines.
Main Results:
- CAPAN-2 cells exhibited significant sensitivity to GGMSC, characterized by the activation of oxidative stress and ferroptosis pathways.
- Downregulation of metabolic and cell cycle genes was observed in GGMSC-sensitive CAPAN-2 cells.
- HPAF-II cells demonstrated limited transcriptional changes and maintained their proliferative and metabolic profiles, indicating resistance to GGMSC.
Conclusions:
- GGMSC induces distinct transcriptomic responses in different PDAC cell lines, highlighting cell-specific sensitivity.
- The activation of oxidative stress and ferroptosis pathways is a key mechanism of GGMSC action in sensitive PDAC cells.
- These findings provide valuable insights into selenium-based therapies for pancreatic cancer and warrant further investigation.
