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Cancer Res. 2019 Jan 1;79(1):133-145. doi: 10.1158/0008-5472.CAN-18-1968. Epub 2018 Oct 24.

PIN1 Maintains Redox Balance via the c-Myc/NRF2 Axis to Counteract Kras-Induced Mitochondrial Respiratory Injury in Pancreatic Cancer Cells.

Liang C#1,2,3,4, Shi S#1,2,3,4, Liu M#5, Qin Y#1,2,3,4, Meng Q1,2,3,4, Hua J1,2,3,4, Ji S1,2,3,4, Zhang Y5, Yang J5, Xu J1,2,3,4, Ni Q1,2,3,4, Li M6, Yu X7,2,3,4.

Author information

1
Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
2
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
3
Shanghai Pancreatic Cancer Institute, Shanghai, China.
4
Pancreatic Cancer Institute, Fudan University, Shanghai, China.
5
Department of Medicine, Department of Surgery, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
6
Department of Medicine, Department of Surgery, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. Min-Li@ouhsc.edu yuxianjun@fudanpci.org.
7
Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China. Min-Li@ouhsc.edu yuxianjun@fudanpci.org.
#
Contributed equally

Abstract

Kras 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. SIGNIFICANCE: 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.

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