RAR-Dependent and RAR-Independent RXR Signaling in Stem-like Glioma Cells
Retinoic acid (RA) exerts pleiotropic effects during neural development and regulates homeostasis in the adult human brain. The RA signal may be transduced through RXR (retinoid-X receptor)-non-permissive RA receptor/RXR heterodimers or through RXR-permissive RXR heterodimers. The significance of RA...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/22/16466 |
| _version_ | 1797458996750188544 |
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| author | Amanda Dabrock Natalie Ernesti Florian Will Manaf Rana Nadja Leinung Phillip Ehrich Volker Tronnier Christina Zechel |
| author_facet | Amanda Dabrock Natalie Ernesti Florian Will Manaf Rana Nadja Leinung Phillip Ehrich Volker Tronnier Christina Zechel |
| author_sort | Amanda Dabrock |
| collection | DOAJ |
| description | Retinoic acid (RA) exerts pleiotropic effects during neural development and regulates homeostasis in the adult human brain. The RA signal may be transduced through RXR (retinoid-X receptor)-non-permissive RA receptor/RXR heterodimers or through RXR-permissive RXR heterodimers. The significance of RA signaling in malignant brain tumors such as glioblastoma multiforme (GBM) and gliosarcoma (GS) is poorly understood. In particular, the impact RA has on the proliferation, survival, differentiation, or metabolism of GBM- or GS-derived cells with features of stem cells (SLGCs) remains elusive. In the present manuscript, six GBM- and two GS-derived SLGC lines were analyzed for their responsiveness to RAR- and RXR-selective agonists. Inhibition of proliferation and initiation of differentiation were achieved with a RAR-selective pan-agonist in a subgroup of SLGC lines, whereas RXR-selective pan-agonists (rexinoids) supported proliferation in most SLGC lines. To decipher the RAR-dependent and RAR-independent effects of RXR, the genes encoding the RAR or RXR isotypes were functionally inactivated by CRISPR/Cas9-mediated editing in an IDH1-/p53-positive SLGC line with good responsiveness to RA. Stemness, differentiation capacity, and growth behavior were preserved after editing. Taken together, this manuscript provides evidence about the positive impact of RAR-independent RXR signaling on proliferation, survival, and tumor metabolism in SLGCs. |
| first_indexed | 2024-03-09T16:45:10Z |
| format | Article |
| id | doaj.art-954969823574480c8759671cfb011714 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T16:45:10Z |
| publishDate | 2023-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-954969823574480c8759671cfb0117142023-11-24T14:47:46ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-11-0124221646610.3390/ijms242216466RAR-Dependent and RAR-Independent RXR Signaling in Stem-like Glioma CellsAmanda Dabrock0Natalie Ernesti1Florian Will2Manaf Rana3Nadja Leinung4Phillip Ehrich5Volker Tronnier6Christina Zechel7Laboratory of Experimental Neuro-Oncology, Center of Brain, Behavior and Metabolism, University Lübeck, Marie-Curie Strasse 66, D-23562 Lübeck, GermanyLaboratory of Experimental Neuro-Oncology, Center of Brain, Behavior and Metabolism, University Lübeck, Marie-Curie Strasse 66, D-23562 Lübeck, GermanyLaboratory of Experimental Neuro-Oncology, Center of Brain, Behavior and Metabolism, University Lübeck, Marie-Curie Strasse 66, D-23562 Lübeck, GermanyLaboratory of Experimental Neuro-Oncology, Center of Brain, Behavior and Metabolism, University Lübeck, Marie-Curie Strasse 66, D-23562 Lübeck, GermanyLaboratory of Experimental Neuro-Oncology, Center of Brain, Behavior and Metabolism, University Lübeck, Marie-Curie Strasse 66, D-23562 Lübeck, GermanyLaboratory of Experimental Neuro-Oncology, Center of Brain, Behavior and Metabolism, University Lübeck, Marie-Curie Strasse 66, D-23562 Lübeck, GermanyDepartment of Neurosurgery, University Clinic Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, D-23538 Lübeck, GermanyLaboratory of Experimental Neuro-Oncology, Center of Brain, Behavior and Metabolism, University Lübeck, Marie-Curie Strasse 66, D-23562 Lübeck, GermanyRetinoic acid (RA) exerts pleiotropic effects during neural development and regulates homeostasis in the adult human brain. The RA signal may be transduced through RXR (retinoid-X receptor)-non-permissive RA receptor/RXR heterodimers or through RXR-permissive RXR heterodimers. The significance of RA signaling in malignant brain tumors such as glioblastoma multiforme (GBM) and gliosarcoma (GS) is poorly understood. In particular, the impact RA has on the proliferation, survival, differentiation, or metabolism of GBM- or GS-derived cells with features of stem cells (SLGCs) remains elusive. In the present manuscript, six GBM- and two GS-derived SLGC lines were analyzed for their responsiveness to RAR- and RXR-selective agonists. Inhibition of proliferation and initiation of differentiation were achieved with a RAR-selective pan-agonist in a subgroup of SLGC lines, whereas RXR-selective pan-agonists (rexinoids) supported proliferation in most SLGC lines. To decipher the RAR-dependent and RAR-independent effects of RXR, the genes encoding the RAR or RXR isotypes were functionally inactivated by CRISPR/Cas9-mediated editing in an IDH1-/p53-positive SLGC line with good responsiveness to RA. Stemness, differentiation capacity, and growth behavior were preserved after editing. Taken together, this manuscript provides evidence about the positive impact of RAR-independent RXR signaling on proliferation, survival, and tumor metabolism in SLGCs.https://www.mdpi.com/1422-0067/24/22/16466malignant gliomaretinoic acid receptorsretinoid-X receptorsynthetic retinoidsCRISPR/Cas9 editing |
| spellingShingle | Amanda Dabrock Natalie Ernesti Florian Will Manaf Rana Nadja Leinung Phillip Ehrich Volker Tronnier Christina Zechel RAR-Dependent and RAR-Independent RXR Signaling in Stem-like Glioma Cells International Journal of Molecular Sciences malignant glioma retinoic acid receptors retinoid-X receptor synthetic retinoids CRISPR/Cas9 editing |
| title | RAR-Dependent and RAR-Independent RXR Signaling in Stem-like Glioma Cells |
| title_full | RAR-Dependent and RAR-Independent RXR Signaling in Stem-like Glioma Cells |
| title_fullStr | RAR-Dependent and RAR-Independent RXR Signaling in Stem-like Glioma Cells |
| title_full_unstemmed | RAR-Dependent and RAR-Independent RXR Signaling in Stem-like Glioma Cells |
| title_short | RAR-Dependent and RAR-Independent RXR Signaling in Stem-like Glioma Cells |
| title_sort | rar dependent and rar independent rxr signaling in stem like glioma cells |
| topic | malignant glioma retinoic acid receptors retinoid-X receptor synthetic retinoids CRISPR/Cas9 editing |
| url | https://www.mdpi.com/1422-0067/24/22/16466 |
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