PIN1 Maintains Redox Balance via the c-Myc/NRF2 Axis to Counteract Kras-Induced Mitochondrial Respiratory Injury in Pancreatic Cancer Cells
PIN1 Maintains Redox Balance via the c-Myc/NRF2 Axis to Counteract Kras-Induced Mitochondrial Respiratory Injury in Pancreatic Cancer Cells
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PIN1 通过 c-Myc/NRF2 轴维持氧化还原平衡，以抵消 Kras 诱导的胰腺癌细胞线粒体呼吸损伤
DOI：
10.1158/0008-5472.can-18-1968
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发表时间：
2019-01-01
期刊：
影响因子：
11.2
通讯作者：
Yu, Xianjun
中科院分区：
文献类型：
--
作者：
Liang, Chen;Shi, Si;Yu, Xianjun
Kras是胰腺导管腺癌（PDAC）的决定性癌基因。PIN 1是参与Kras/ERK轴的关键效应子，协同介导各种细胞事件。然而，PIN 1促进PDAC发展的潜在机制仍不清楚。在这里，我们试图阐明PIN 1对Kras驱动的PDAC中氧化还原稳态的影响。PIN 1在PDAC中表达上调，可预测疾病的预后，尤其是Kras突变型PDAC。PIN 1的下调抑制PDAC细胞生长并促进凋亡，部分原因是线粒体功能障碍。PIN 1的沉默通过显著增加细胞内ROS而损害线粒体的基础功能。此外，PIN 1通过协同激活c-Myc和NRF 2来维持氧化还原平衡，以上调PDAC细胞中抗氧化反应元件驱动基因的表达。这项研究阐明了一种新的机制，Kras/ERK/NRF 2促进肿瘤生长，并确定PIN 1作为一个决定性的目标，在治疗策略，旨在扰乱氧化还原平衡在胰腺cancer.Significance：这项研究表明，抗氧化保护Kras突变胰腺癌细胞的氧化损伤，这可能有助于发展的一个有针对性的治疗策略，为Kras驱动的PDAC通过损害氧化还原稳态。
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.