Please use this identifier to cite or link to this item:
http://doi.org/10.25358/openscience-8158
Authors: | Geiß, Carsten Witzler, Claudius Poschet, Gernot Ruf, Wolfram Régnier-Vigouroux, Anne |
Title: | Metabolic and inflammatory reprogramming of macrophages by ONC201 translates in a pro-inflammatory environment even in presence of glioblastoma cells |
Online publication date: | 17-Nov-2022 |
Year of first publication: | 2021 |
Language: | english |
Abstract: | Tumor-associated macrophages facilitate tumor progression and resistance to therapy. Their capacity for metabolic and inflammatory reprogramming represents an attractive therapeutic target. ONC201/TIC10 is an anticancer molecule that antagonizes the dopamine receptor D2 and affects mitochondria integrity in tumor cells. We examined whether ONC201 induces a metabolic and pro-inflammatory switch in primary human monocyte-derived macrophages that reactivates their antitumor activities, thus enhancing the onco-toxicity of ONC201. Contrary to glioblastoma cells, macrophages exhibited a low ratio of dopamine receptors D2/D5 gene expression and were resistant to ONC201 cytotoxicity. Macrophages responded to ONC201 with a severe loss of mitochondria integrity, a switch to glycolytic ATP production, alterations in glutamate transport, and a shift towards a pro-inflammatory profile. Treatment of macrophages–glioblastoma cells co-cultures with ONC201 induced similar alterations in glutamatergic and inflammatory gene expression profiles of macrophages. It induced as well metabolic changes and a pro-inflammatory switch of the co-culture milieu. However, these changes did not translate into increased onco-toxicity. This study provides the first evidence that ONC201 affects macrophage immunometabolism and leads to a pro-inflammatory tumor environment. This speaks in favor of implementing ONC201 in combinatorial therapies and warrants further investigation of the mechanisms of action of ONC201 in macrophages and other immune cells. |
DDC: | 570 Biowissenschaften 570 Life sciences 610 Medizin 610 Medical sciences |
Institution: | Johannes Gutenberg-Universität Mainz |
Department: | FB 04 Medizin FB 10 Biologie |
Place: | Mainz |
ROR: | https://ror.org/023b0x485 |
DOI: | http://doi.org/10.25358/openscience-8158 |
Version: | Published version |
Publication type: | Zeitschriftenaufsatz |
License: | CC BY-NC |
Information on rights of use: | https://creativecommons.org/licenses/by-nc/4.0/ |
Journal: | European journal of immunology 51 5 |
Pages or article number: | 1246 1261 |
Publisher: | Wiley-VCH |
Publisher place: | Weinheim |
Issue date: | 2021 |
ISSN: | 1521-4141 |
Publisher DOI: | 10.1002/eji.202048957 |
Appears in collections: | JGU-Publikationen |
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File | Description | Size | Format | ||
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![]() | metabolic_and_inflammatory_re-20221117095533328.pdf | 786.96 kB | Adobe PDF | View/Open |