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

Chen Liang,Qingcai Meng,Shunrong Ji,Si Shi,Min Li,Mingyang Liu,Yuqing Zhang,Jingxuan Yang,Jie Hua,Jin Xu,Quanxing Ni,Yi Qin,Xianjun Yu

doi:10.1158/0008-5472.can-18-1968

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.

Highlights

Pancreatic cancer is one of the most lethal malignancies, with an overall 5-year survival rate of less than 8% [1]
Given the oncogenic effect of Protein interacting with never in mitosis A1 (PIN1) on pancreatic tumorigenesis, we demonstrate that PIN1 protects the basal mitochondrial function from Kras/ERKinduced oxidative injury and maintains the redox balance in Pancreatic ductal adenocarcinoma (PDAC) by increasing the expression of antioxidant response element (ARE)-driven genes
To determine whether the predictive effect of PIN1 on survival depended on the Kras mutation, we examined 70 patients with PDAC to perform Kras mutation testing

Summary

Introduction

Pancreatic cancer is one of the most lethal malignancies, with an overall 5-year survival rate of less than 8% [1]. Pancreatic ductal adenocarcinoma (PDAC) is the major histologic type, accounting for >95% of human pancreatic neoplasms [2]. Oncogenic Kras mutations occur early in PDAC carcinogenesis and are observed in more than 90% of PDAC cases [3]. There is an urgent need to explore the underlying mechanism and downstream effectors of the constitutive activation of the Kras proto-. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

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