Supplementary Table S1 showed the clinicopathological features and correlation of PIN1 expression in PDAC tissue samples. Supplementary Table S2 showed the human primers for quantitative PCR. Supplementary Table S3 showed the primers for Chromatin Immunoprecipitation (ChIP) assays. Supplementary Table S4. Showed the correlation of Kras status and PIN1 expression in PDAC patients. Supplementary Table S5 showed the correlation of ERK activation and PIN1 expression in PDAC patients. Supplementary Table S6 showed the Kras mutant status in the pancreatic cancer cell lines and HPDE examined in our study.
National Science Fund Distinguished Young Scholars of China
National Natural Sciences Foundation of China
Shanghai Sailing Program
ARTICLE ABSTRACTKras is a decisive oncogene in pancreatic ductal adenocarcinoma (PDAC). PIN1 is a key effector involved in the Kras/ERK axis, synergistically mediating various cellular events. However, the underlying mechanism by which PIN1 promotes the development of PDAC remains unclear. Here we sought to elucidate the effect of PIN1 on redox homeostasis in Kras-driven PDAC. PIN1 was prevalently upregulated in PDAC and predicted the prognosis of the disease, especially Kras-mutant PDAC. Downregulation of PIN1 inhibited PDAC cell growth and promoted apoptosis, partially due to mitochondrial dysfunction. Silencing of PIN1 damaged basal mitochondrial function by significantly increasing intracellular ROS. Furthermore, PIN1 maintained redox balance via synergistic activation of c-Myc and NRF2 to upregulate expression of antioxidant response element driven genes in PDAC cells. This study elucidates a new mechanism by which Kras/ERK/NRF2 promotes tumor growth and identifies PIN1 as a decisive target in therapeutic strategies aimed at disturbing the redox balance in pancreatic cancer.
This study suggests that antioxidation protects Kras-mutant pancreatic cancer cells from oxidative injury, which may contribute to development of a targeted therapeutic strategy for Kras-driven PDAC by impairing redox homeostasis.