Generation of Hydrogen Peroxide and Downstream Protein Kinase D1 Signaling Is a Common Feature of Inducers of Pancreatic Acinar-to-Ductal Metaplasia

Abstract

Pancreatic acinar-to-ductal metaplasia (ADM) is a reversible process that occurs after pancreatic injury, but becomes permanent and leads to pancreatic lesions in the presence of an oncogenic mutation in KRAS. While inflammatory macrophage-secreted chemokines, growth factors that activate epidermal growth factor receptor (EGFR) and oncogenic KRAS have been implicated in the induction of ADM, it is currently unclear whether a common underlying signaling mechanism exists that drives this process. In this study, we show that different inducers of ADM increase levels of hydrogen peroxide, most likely generated at the mitochondria, and upregulate the expression of Protein Kinase D1 (PKD1), a kinase that can be activated by hydrogen peroxide. PKD1 expression in acinar cells affects their survival and mediates ADM, which is in part due to the PKD1 target NF-κB. Overall, our data implicate ROS-PKD1 signaling as a common feature of different inducers of pancreatic ADM.

Macrophage-induced reactive oxygen species in the initiation of pancreatic cancer: a mini-review

“…Pro-inflammatory macrophages are the major immune cell population driving the formation of ADM lesions ( 10 , 16 , 17 ), and their crucial role in this process was demonstrated in vivo (in mice) by genetic ablation and by chemical depletion ( 10 , 20 ). Using the KC (p48 Cre ;LSL- Kras G12D ) mouse model it was shown that during the development of pancreatic cancer these macrophages accumulate rapidly in ADM regions ( 21 ).…”

“…Moreover, M2 macrophages can drive ADM through CCL2 ( 17 ). All these factors have in common that they induce hydrogen peroxide in acinar cells, which was shown to be the major driver of ADM ( 16 , 17 ). Hydrogen peroxide most likely originates at the mitochondria, since mitochondrially-targeted catalase or the antioxidant MitoQ can block the initiation of ADM ( 16 ).…”

“…Although it is still unclear how above macrophage-secreted factors induce ROS at the mitochondria, studies with mitochondrially-targeted antioxidants link ROS responsive signaling cascades and transcriptional activation to ADM. One of the main inducers of ADM downstream of mitochondrial ROS is the PKD1/NF-κB signaling cascade ( 16 , 26 , 33 ). Other transcription factors that have been demonstrated to be predominant drivers of ADM are Notch, Signal Transducer and Activator of Transcription 3 (STAT3), Kruppel-like factor 4 (KLF4) and Nuclear Factor of Activated T Cells 1/4 (NFAT1/4) ( 34 – 38 ).…”

Roles of differently polarized macrophages in the initiation and progressionof pancreatic cancer

“…ADM can be initiated by the M1-secreted factors TNFα, CCL5/RANTES, IL-1α and IL-6 ( 12 , 34 ). A common underlying signaling event that these factors are activating in acinar cells is the increase in mitochondrially-generated reactive oxygen species (mROS) ( 35 ), which then drive ADM through transcriptional upregulation of EGFR and its ligands ( 36 ). It should be noted that oncogenic KRAS by itself is a weak inducer of ADM in ex vivo (explant) studies, also by increasing intracellular levels of mitochondrial oxidative stress and expression of EGFR ( 36 ).…”

Oxidative Stress in Chronic and Age-Related Diseases

“…The study by Döppler and colleagues [4] concerned oxidative stress and inflammation in pancreatic acinar-to-ductal metaplasia (ADM), a reversible process that occurs after pancreatic injury but becomes permanent and leads to pancreatic lesions in the presence of oncogenic mutations. In this study, the authors identified the generation of mitochondrial ROS as a common signaling pathway for the inducers of ADM.…”