Abstract
BackgroundReactive oxygen species (ROS), including hydrogen peroxide, drive differentiation of normal fibroblasts into activated fibroblasts, which can generate high amounts of hydrogen peroxide themselves, thereby increasing oxidative stress in the microenvironment. This way, activated fibroblasts can transition into cancer-associated fibroblasts (CAFs).MethodsMammary fibroblasts from either female 8 weeks old PRDX1 knockout and wildtype mice or Balb/c mice were studied for characteristic protein expression using immunofluorescence and immunoblotting. Cancer-associated fibroblasts was examined by transwell migration and invasion assays. The binding of PRDX1 to JNK1 was assessed by co-immuneprecipitation and JNK regulation of CAF phenotypes was examined using the JNK inhibitor SP600125. Extracellular hydrogen peroxide levels were measured by chemiluminescence via the reaction between hypochlorite and luminol. Statistical analyses were done using Students t-test.ResultsWe show here PRDX1 activity as an essential switch in regulating the activated phenotype as loss of PRDX1 results in the development of a CAF-like phenotype in mammary fibroblasts. We also show that PRDX1 regulates JNK kinase signaling thereby inhibiting CAF-like markers and CAF invasion. Inhibition of JNK activity reduced these behaviors.ConclusionsThese data suggest that PRDX1 repressed the activated phenotype of fibroblasts in part through JNK inhibition which may present a novel therapeutic option for CAF-enriched cancers such as breast cancer.
Highlights
Reactive oxygen species (ROS), including hydrogen peroxide, drive differentiation of normal fibroblasts into activated fibroblasts, which can generate high amounts of hydrogen peroxide themselves, thereby increasing oxidative stress in the microenvironment
To define a potential role for PRDX1 in regulating the activated phenotype in fibroblasts, we investigated Murine embryonic fibroblasts (MEFs) isolated from PRDX1 knockout (Prdx1−/−) and wild-type (Prdx1+/+) embryos [25] for characteristic expression of activated fibroblast and cancer-associated fibroblasts (CAFs)
We examined whether loss of PRDX1 in mammary fibroblasts (MF) led to phenotypic characteristics that resemble cancer-associated fibroblasts (CAFs) [3, 27]
Summary
Reactive oxygen species (ROS), including hydrogen peroxide, drive differentiation of normal fibroblasts into activated fibroblasts, which can generate high amounts of hydrogen peroxide themselves, thereby increasing oxidative stress in the microenvironment. This way, activated fibroblasts can transition into cancer-associated fibroblasts (CAFs). Fibroblasts are the most abundant cell type in connective tissue. There, they form the structural network by secreting extracellular matrix components. Once the wound is closed, activated fibroblasts or myofibrobalsts undergo cell death in the form of apoptosis. Mechanistic details on how oxidants promote the CAF phenotype are still unclear though, as the mammary gland is a stroma rich organ, elucidation of signaling proteins regulated by H2O2 is essential to combat CAF function in breast cancer
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