TY  - JOUR
A1  - Hohenester, Simon
A1  - Kanitz, Veronika
A1  - Schiergens, Tobias
A1  - Einer, Claudia
A1  - Nagel, Jutta
A1  - Wimmer, Ralf
A1  - Reiter, Florian P.
A1  - Gerbes, Alexander L.
A1  - De Toni, Enrico N.
A1  - Bauer, Christian
A1  - Holdt, Lesca
A1  - Mayr, Doris
A1  - Rust, Christian
A1  - Schnurr, Max
A1  - Zischka, Hans
A1  - Geier, Andreas
A1  - Denk, Gerald
T1  - IL-18 but not IL-1 signaling is pivotal for the initiation of liver injury in murine non-alcoholic fatty liver disease
JF  - International Journal of Molecular Sciences
N2  - Non-alcoholic fatty liver disease (NAFLD) is rising in prevalence, and a better pathophysiologic understanding of the transition to its inflammatory phenotype (NASH) is key to the development of effective therapies. To evaluate the contribution of the NLRP3 inflammasome and its downstream effectors IL-1 and IL-18 in this process, we applied the true-to-life “American lifestyle-induced obesity syndrome” (ALiOS) diet mouse model. Development of obesity, fatty liver and liver damage was investigated in mice fed for 24 weeks according to the ALiOS protocol. Lipidomic changes in mouse livers were compared to human NAFLD samples. Receptor knockout mice for IL-1 and IL-18 were used to dissect the impact of downstream signals of inflammasome activity on the development of NAFLD. The ALiOS diet induced obesity and liver steatosis. The lipidomic changes closely mimicked changes in human NAFLD. A pro-inflammatory gene expression pattern in liver tissue and increased serum liver transaminases indicated early liver damage in the absence of histological evidence of NASH. Mechanistically, Il-18r\(^{−/−}\)- but not Il-1r\(^{−/−}\) mice were protected from early liver damage, possibly due to silencing of the pro-inflammatory gene expression pattern. Our study identified NLRP3 activation and IL-18R-dependent signaling as potential modulators of early liver damage in NAFLD, preceding development of histologic NASH.
KW  - NAFLD
KW  - Western diet
KW  - NLRP3
KW  - inflammasome
KW  - interleukin 1
KW  - interleukin 18
KW  - NASH
KW  - ALiOS
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285221
SN  - 1422-0067
VL  - 21
IS  - 22
ER  - 
TY  - JOUR
A1  - Ben Khaled, Najib
A1  - Hammer, Katharina
A1  - Ye, Liangtao
A1  - Alnatsha, Ahmed
A1  - Widholz, Sebastian A.
A1  - Piseddu, Ignazio
A1  - Sirtl, Simon
A1  - Schneider, Julia
A1  - Munker, Stefan
A1  - Mahajan, Ujjwal Mukund
A1  - Montero, Juan José
A1  - Griger, Joscha
A1  - Mayerle, Julia
A1  - Reiter, Florian P.
A1  - De Toni, Enrico N.
T1  - TRAIL receptor targeting agents potentiate PARP inhibitor efficacy in pancreatic cancer independently of BRCA2 mutation status
JF  - Cancers
N2  - Chemotherapy, the standard treatment for pancreatic ductal adenocarcinoma (PDAC), has only a modest effect on the outcome of patients with late-stage disease. Investigations of the genetic features of PDAC have demonstrated a frequent occurrence of mutations in genes involved in homologous recombination (HR), especially in the breast cancer susceptibility gene 2 (BRCA2). Olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, is approved as a maintenance treatment for patients with advanced PDAC with germline BRCA1/2 mutations following a platinum-containing first-line regimen. Limitations to the use of PARP inhibitors are represented by the relatively small proportion of patients with mutations in BRCA1/2 genes and the modest capability of these substances of inducing objective response. We have previously shown that pancreatic cancer with BRCA2 mutations exhibits a remarkably enhanced sensitivity towards tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL) receptor-stimulating agents. We thus aimed to investigate the effect of combined treatment with PARP inhibitors and TRAIL receptor-stimulating agents in pancreatic cancer and its dependency on the BRCA2 gene status. The respective effects of TRAIL-targeting agents and the PARP inhibitor olaparib or of their combination were assessed in pancreatic cancer cell lines and patient-derived organoids. In addition, BRCA2-knockout and -complementation models were investigated. The effects of these agents on apoptosis, DNA damage, cell cycle, and receptor surface expression were assessed by immunofluorescence, Western blot, and flow cytometry. PARP inhibition and TRAIL synergized to cause cell death in pancreatic cancer cell lines and PDAC organoids. This effect proved independent of BRCA2 gene status in three independent models. Olaparib and TRAIL in combination caused a detectable increase in DNA damage and a concentration-dependent cell cycle arrest in the G2/M and S cell cycle phases. Olaparib also significantly increased the proportion of membrane-bound death receptor 5. Our results provide a preclinical rationale for the combination of PARP inhibitors and TRAIL receptor agonists for the treatment of pancreatic cancer and suggest that the use of PARP inhibitors could be extended to patients without BRCA2 mutations if used in combination with TRAIL agonists.
KW  - apoptosis
KW  - DNA damage
KW  - pancreatic neoplasms
KW  - poly(ADP-ribose) polymerase inhibitors
KW  - TNF-related apoptosis-inducing ligand
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290884
SN  - 2072-6694
VL  - 14
IS  - 21
ER  -