1. The BRD4 Inhibitor I-BET-762 Reduces HO-1 Expression in Macrophages and the Pancreas of Mice.
- Author
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Leal AS and Liby KT
- Subjects
- Animals, Mice, Pancreas metabolism, Pancreas pathology, Pancreas drug effects, Humans, Pancreatitis metabolism, Pancreatitis drug therapy, Pancreatitis genetics, Mice, Knockout, Tumor Microenvironment drug effects, Cell Cycle Proteins metabolism, Cell Cycle Proteins genetics, Cell Line, Tumor, Mice, Inbred C57BL, Bromodomain Containing Proteins, Membrane Proteins, Nuclear Proteins, Heme Oxygenase-1 metabolism, Heme Oxygenase-1 genetics, Macrophages metabolism, Macrophages drug effects, NF-E2-Related Factor 2 metabolism, NF-E2-Related Factor 2 genetics, Transcription Factors metabolism, Transcription Factors genetics, Pancreatic Neoplasms metabolism, Pancreatic Neoplasms genetics, Pancreatic Neoplasms pathology, Pancreatic Neoplasms drug therapy
- Abstract
In pancreatic cancer, the tumor microenvironment (TME) accounts for up to 90% of the tumor mass. Pancreatitis, characterized by the increased infiltration of macrophages into the pancreas, is a known risk factor for pancreatic cancer. The NRF2 (nuclear factor erythroid 2-related factor 2) transcription factor regulates responses to oxidative stress and can promote cancer and chemoresistance. NRF2 also attenuates inflammation through the regulation of macrophage-specific genes. Heme oxygenase 1 (HO-1) is expressed by anti-inflammatory macrophages to degrade heme, and its expression is dependent on NRF2 translocation to the nucleus. In macrophages stimulated with conditioned media from pancreatic cancer cells, HO-1 protein levels increased, which correlated with higher NRF2 expression in the nuclear fraction. Significant differences in macrophage infiltration and HO-1 expression were detected in LSL-Kras
G12D/+ ; Pdx-1-Cre (KC) mice, Nrf2 whole-body knockout (KO) mice and wildtype mice with pancreatitis. Since epigenetic modulation is a mechanism used by tumors to regulate the TME, using small molecules as epigenetic modulators to activate immune recognition is therapeutically desirable. When the bromodomain inhibitor I-BET-762 was used to treat macrophages or mice with pancreatitis, high levels of HO-1 were reduced. This study shows that bromodomain inhibitors can be used to prevent physiological responses to inflammation that promote tumorigenesis.- Published
- 2024
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