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Pirfenidone inhibits TGF-beta expression in malignant glioma cells
Isabel Burghardt1, Felix Tritschler, Christiane A Opitz
1Laboratory of Molecular Neuro-Oncology, Department of General Neurology and Hertie Institute for Clinical Brain Research, University of Tübingen, Hoppe-Seyler-Strasse 3, D-72076, Tübingen, Germany.
Abstract:
Due to its immunosuppressive properties, the cytokine transforming growth factor (TGF)-beta has become a promising target in the experimental treatment of human malignant gliomas. Here, we report that the antifibrotic drug 5-methyl-1-phenyl-2-(1H)-pyridone (pirfenidone, PFD) elicits growth-inhibitory effects and reduces TGF-beta2 protein levels in human glioma cell lines. This reduction in TGF-beta2 is biologically relevant since PFD treatment reduces the growth inhibition of TGF-beta-sensitive CCL-64 cells mediated by conditioned media of glioma cells. The downregulation of TGF-beta is mediated at multiple levels. PFD leads to a reduction of TGF-beta2 mRNA levels and of the mature TGF-beta2 protein due to decreased expression and direct inhibition of the TGF-beta pro-protein convertase furin. In addition, PFD reduces the protein levels of the matrix metalloproteinase (MMP)-11, a TGF-beta target gene and furin substrate involved in carcinogenesis. These data define PFD or PFD-related agents as promising agents for human cancers associated with enhanced TGF-beta activity.
Insights
The antifibrotic drug pirfenidone (PFD) inhibits human glioma cell growth and reduces transforming growth factor-beta2 (TGF-beta2). PFD targets TGF-beta2 at multiple levels, showing promise for treating TGF-beta-associated cancers.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Transforming growth factor-beta (TGF-beta) has immunosuppressive properties, making it a target for malignant glioma treatment.
- Pirfenidone (PFD) is an antifibrotic drug with potential anti-cancer applications.
Purpose of the Study:
- To investigate the effects of pirfenidone (PFD) on human glioma cell lines.
- To determine if PFD can reduce transforming growth factor-beta2 (TGF-beta2) levels and activity in gliomas.
Main Methods:
- Assessed PFD's impact on glioma cell proliferation and TGF-beta2 protein levels.
- Investigated PFD's effect on TGF-beta2 mRNA expression and furin activity.
- Examined PFD's influence on matrix metalloproteinase (MMP)-11 expression.
Main Results:
- Pirfenidone (PFD) demonstrated growth-inhibitory effects on human glioma cells.
- PFD significantly reduced TGF-beta2 protein and mRNA levels.
- PFD inhibited furin, a key enzyme in TGF-beta processing, and decreased MMP-11 levels.
Conclusions:
- Pirfenidone (PFD) effectively downregulates TGF-beta2 signaling in human gliomas via multiple mechanisms.
- PFD and related agents show potential for treating cancers characterized by elevated TGF-beta activity.
