Impaired Autophagy Induces Chronic Atrophic Pancreatitis in Mice via Sex- and Nutrition-Dependent Processes

Diakopoulos, Kalliope N.; Lesina, Marina; Wörmann, Sonja M.; Song, Lina; Aichler, Michaela; Schild, Lorenz; Artati, Anna; Römisch-Margl, Werner; Wartmann, Thomas; Fischer, Reinhard; Kabiri, Yaschar; Zischka, Hans; Halangk, Walter; Demir, Ihsan Ekin; Pilsak, Claudia; Walch, Axel; Mantzoros, Christos S.; Steiner, Jörg M.; Erkan, Mert; Schmid, Roland M.; Witt, Heiko; Adamski, Jerzy; Algül, Hana

doi:10.1053/j.gastro.2014.12.003

Cited by 141 publications

(176 citation statements)

References 34 publications

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“…Unlike previously described Ikkα Δpan and Atg5 Δpan mice, which exhibit autophagy defects that can be ameliorated by the loss of p62 (15,16), the more severe pancreatitis and acinar tissue atrophy in Atg7 Δpan mice cannot be rescued by additional p62 ablation. These findings also stand in marked contrast to those reported in an earlier study in which Atg5 was ablated using Cre recombinase driven by the elastase promoter (13).…”

Section: Discussioncontrasting

confidence: 75%

“…Intrapancreatic trypsin activity was elevated at an early (4 wk) but not at a later (12 wk) time point (Fig. 2D), suggesting that premature, intraacinar, trypsinogen activation is just one of several factors that contribute to this disease (15,16). Collectively, these results indicate that loss of ATG7 triggers pancreatic atrophy, fibrosis, and chronic pancreatitis.…”

Section: Resultsmentioning

confidence: 90%

“…Conversely, loss of autophagy can result in progressive loss of pancreatic function, which leads to development of pancreatitis as well as regenerative responses that may increase the risk of pancreatic cancer. Ptf1a-Cre; Atg5 F/F ) have demonstrated that insufficient autophagy, at least in mice, can lead to the onset of pancreatitis (15)(16)(17). The mechanisms by which disruption of autophagy triggers pancreatitis are poorly understood.…”

mentioning

confidence: 99%

“…IKKα deficiency impairs the completion of autophagy in acinar cells, with accumulation of the chaperon and autophagy substrate ubiquitin-binding protein p62/SQSTM1 as the key pathogenic mechanism (15). However, ablation of ATG5 was reported to either inhibit (13) or promote (16) pancreatitis. In addition, inhibition of autophagy can either accelerate the development of early malignant lesions in mice lacking the transformation-related protein 53 (p53) (19) or cause the death of established pancreatic cancer (20).…”

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confidence: 99%

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Basal autophagy maintains pancreatic acinar cell homeostasis and protein synthesis and prevents ER stress

Antonucci

Fagman

Kim

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

208

182

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Pancreatic acinar cells possess very high protein synthetic rates as they need to produce and secrete large amounts of digestive enzymes. Acinar cell damage and dysfunction cause malnutrition and pancreatitis, and inflammation of the exocrine pancreas that promotes development of pancreatic ductal adenocarcinoma (PDAC), a deadly pancreatic neoplasm. The cellular and molecular mechanisms that maintain acinar cell function and whose dysregulation can lead to tissue damage and chronic pancreatitis are poorly understood. It was suggested that autophagy, the principal cellular degradative pathway, is impaired in pancreatitis, but it is unknown whether impaired autophagy is a cause or a consequence of pancreatitis. To address this question, we generated Atg7 Δpan mice that lack the essential autophagy-related protein 7 (ATG7) in pancreatic epithelial cells. Atg7 Δpan mice exhibit severe acinar cell degeneration, leading to pancreatic inflammation and extensive fibrosis. Whereas ATG7 loss leads to the expected decrease in autophagic flux, it also results in endoplasmic reticulum (ER) stress, accumulation of dysfunctional mitochondria, oxidative stress, activation of AMPK, and a marked decrease in protein synthetic capacity that is accompanied by loss of rough ER. Atg7 Δpan mice also exhibit spontaneous activation of regenerative mechanisms that initiate acinar-to-ductal metaplasia (ADM), a process that replaces damaged acinar cells with duct-like structures.T he pancreatic acinar cell is responsible for production and secretion of numerous digestive enzymes, including amylase, lipase, and various proteases. To cope with the high daily demand for these enzymes, the acinar cell possesses one of the highest protein biosynthetic rates of all cells, together with an extensive rough endoplasmic reticulum (RER) network (1). Due to its high protein synthetic rates, the acinar cell is prone to the accumulation of misfolded proteins and subsequent induction of ER stress (2, 3). ER stress was suggested to be involved in the pathogenesis of pancreatitis, a potentially fatal inflammatory disease of the exocrine pancreas (2, 4). By progressing from acute (sudden onset; duration <6 mo), to recurrent acute (>1 episode of acute pancreatitis), and chronic (duration >6 mo) disease (5), pancreatitis increases the risk of pancreatic ductal adenocarcinoma (PDAC), the fourth deadliest cancer worldwide, with a median survival of 6 mo (6). The molecular mechanisms mediating the progression of pancreatitis from acinar cell damage and inflammation to formation of pancreatic intraepithelial neoplasia (PanIN) and PDAC are not fully understood. Recent studies suggest that in addition to ER stress, insufficient autophagy also contributes to development of pancreatitis (7).Autophagy is an evolutionarily conserved, catabolic quality control process that maintains cellular homeostasis by degrading damaged organelles, misfolded protein aggregates, and foreign organisms (8). Autophagy is also important for generation of amino acids and other building blo...

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Section: Discussioncontrasting

confidence: 75%

Section: Resultsmentioning

confidence: 90%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Basal autophagy maintains pancreatic acinar cell homeostasis and protein synthesis and prevents ER stress

Antonucci

Fagman

Kim

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

208

182

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“…In murine oncogenic Kras -induced lung cancer, Atg7 deficiency upregulated multiple cytokines (12), and Atg5 loss resulted in Treg accumulation (13). Pancreatic Atg5 inactivation itself increased inflammation and acinar-to-ductal metaplasia (ADM), causing atrophic chronic pancreatitis (15). Proteomic analyses in PDAC cell lines following autophagy inhibition also identified upregulation of Tank-binding kinase 1 (TBK1) and interferon gamma receptor 1 (IFNGR1), among other inflammatory signaling components (16,17).…”

Section: Introductionmentioning

confidence: 99%

Autophagy Inhibition Dysregulates TBK1 Signaling and Promotes Pancreatic Inflammation

Yang

Imamura

Jenkins

et al. 2016

Cancer Immunology Research

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Autophagy promotes tumor progression downstream of oncogenic KRAS, yet also restrains inflammation and dysplasia through mechanisms that remain incompletely characterized. Understanding the basis of this paradox has important implications for the optimal targeting of autophagy in cancer. Using a mouse model of cerulein-induced pancreatitis, we found that loss of autophagy by deletion of Atg5 enhanced activation of the IκB kinase (IKK) related kinase TBK1 in vivo, associated with increased neutrophil and T cell infiltration and PD-L1 upregulation. Consistent with this observation, pharmacologic or genetic inhibition of autophagy in pancreatic ductal adenocarcinoma (PDAC) cells, including suppression of the autophagy receptors NDP52 or p62, prolonged TBK1 activation and increased expression of CCL5, IL6, and several other T-cell and neutrophil chemotactic cytokines in vitro. Defective autophagy also promoted PD-L1 upregulation, which is particularly pronounced downstream of IFNγ signaling and involves JAK pathway activation. Treatment with the TBK1/IKKε/JAK inhibitor CYT387 (also known as momelotinib) not only inhibits autophagy, but also suppresses this feedback inflammation and reduces PD-L1 expression, limiting KRAS-driven pancreatic dysplasia. These findings could contribute to the dual role of autophagy in oncogenesis and have important consequences for its therapeutic targeting.

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Autophagy at the intersection of aging, senescence, and cancer

Cassidy

Narita

2022

Molecular Oncology

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Autophagy is an evolutionarily conserved cellular process in which macromolecules undergo lysosomal degradation. It fulfills essential roles in quality controlling cellular constituents and in energy homeostasis. Basal autophagy is also widely accepted to provide a protective role in aging and aging-related disorders, and its decline with age might precipitate the onset of a variety of diseases. In this review, we discuss the role of basal autophagy in maintaining homeostasis, in part through the maintenance of stem cell populations and the prevention of cellular senescence. We also consider how stress-induced senescence, for example, during oncogene activation and in premalignant disease, might rely on autophagy, and the possibility that the age-associated decline in autophagy might promote tumour development through a variety of mechanisms. Ultimately, evidence suggests that autophagy is required for malignant cancer progression in a number of settings. Thus, autophagy appears to be tumour-suppressive during the early stages of tumorigenesis and tumour-promoting at later stages.

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Impaired Autophagy Induces Chronic Atrophic Pancreatitis in Mice via Sex- and Nutrition-Dependent Processes

Cited by 141 publications

References 34 publications

Basal autophagy maintains pancreatic acinar cell homeostasis and protein synthesis and prevents ER stress

Basal autophagy maintains pancreatic acinar cell homeostasis and protein synthesis and prevents ER stress

Autophagy Inhibition Dysregulates TBK1 Signaling and Promotes Pancreatic Inflammation

Autophagy at the intersection of aging, senescence, and cancer

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