Investigating the Molecular Impact of GGMSC on Redox and Metabolic Pathways in Pancreatic Cancer Cells

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. ?-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. Overall design: RNA-seq of pancreatic ductal adenocarcinoma (PDAC) cell line, CAPAN-2 was performed to assess differential gene expression induced by 500 µM GGMSC at 8 h and 20 h.

胰腺导管腺癌（Pancreatic ductal adenocarcinoma, PDAC）仍是一种极具侵袭性的恶性肿瘤，治疗选择十分有限。靶向代谢脆弱性、阻断氧化还原应激通路作为潜在治疗策略，正受到日益广泛的关注。γ-谷氨酰-硒甲基硒代半胱氨酸（γ-Glutamyl-selenomethylselenocysteine, GGMSC）是一种含硒化合物，其结构与硒代-L-甲基硒代半胱氨酸（seleno-L-methylselenocysteine, MSC）相近，后者在临床前模型中已展现出抗癌潜力，但GGMSC在胰腺导管腺癌中的分子效应尚未得到明确阐释。
本研究探究了两种胰腺导管腺癌细胞系CAPAN-2与HPAF-II对高剂量GGMSC的转录组响应。通过RNA测序与细胞毒性实验发现，CAPAN-2细胞对GGMSC呈现显著敏感性，该敏感性与氧化应激及铁死亡（ferroptosis）相关通路的激活，以及代谢与细胞周期基因的下调紧密关联。与之相反，HPAF-II细胞仅出现有限的转录组改变，并维持了自身的增殖与代谢程序。
本研究结果揭示了GGMSC诱导的胰腺导管腺癌细胞转录响应的分子机制，并为未来开展基于硒的胰腺癌治疗研究提供了潜在方向。
整体实验设计：本研究对胰腺导管腺癌细胞系CAPAN-2进行RNA测序，以评估500 μM GGMSC分别处理8小时与20小时后所诱导的差异基因表达。