Duttenhefner Jenna N, Singh Rahul R, Schmidt Katherine, Reindl Katie M
Department of Biological Sciences, North Dakota State University, Fargo, ND 58102, USA.
Biol Open. 2025 Aug 15;14(8). doi: 10.1242/bio.061986. Epub 2025 Aug 14.
Glutathione S transferase pi-1 (GSTP1) is a detoxification enzyme essential for oxidative homeostasis. In cancer, GSTP1 has been implicated in tumorigenicity, cell cycle progression, and chemoresistance. While GSTP1 depletion has been associated with decreased cancer growth in various models, the mechanism remains poorly understood. This study investigates GSTP1 as a therapeutic target for pancreatic ductal adenocarcinoma (PDAC) using inducible knockdown models. We demonstrate that GSTP1 loss disrupts redox balance, impairs cell survival, and induces metabolic adaptations. Multiomics analysis characterized the global impact of inducible GSTP1 knockdown on the transcriptome and proteome of PDAC cells, identifying 550 differentially expressed genes and 62 proteins. Notably, 43 of these showed consistent regulation at both the mRNA and protein levels. We identify dysregulation of key stress response proteins, including dimethylarginine dimethylaminohydrolase 1 (DDAH1), involved in nitric oxide metabolism, and protein disulfide isomerase A6 (PDIA6), which maintains protein homeostasis. The interplay between GSTP1, DDAH1 and PDIA6 highlights the complexity of redox regulation in pancreatic cancer and suggests that targeting GSTP1 may offer a new therapeutic approach for PDAC.
谷胱甘肽S转移酶pi-1（GSTP1）是氧化稳态所必需的解毒酶。在癌症中，GSTP1与肿瘤发生、细胞周期进程和化疗耐药性有关。虽然在各种模型中，GSTP1的缺失与癌症生长的减少有关，但其机制仍知之甚少。本研究使用诱导性敲低模型研究GSTP1作为胰腺导管腺癌（PDAC）的治疗靶点。我们证明，GSTP1的缺失会破坏氧化还原平衡，损害细胞存活，并诱导代谢适应。多组学分析表征了诱导性GSTP1敲低对PDAC细胞转录组和蛋白质组的整体影响，鉴定出550个差异表达基因和62种蛋白质。值得注意的是，其中43个在mRNA和蛋白质水平上均表现出一致的调控。我们确定了关键应激反应蛋白的失调，包括参与一氧化氮代谢的二甲基精氨酸二甲胺水解酶1（DDAH1）和维持蛋白质稳态的蛋白质二硫键异构酶A6（PDIA6）。GSTP1、DDAH1和PDIA6之间的相互作用突显了胰腺癌氧化还原调节的复杂性，并表明靶向GSTP1可能为PDAC提供一种新的治疗方法。
