Blood glutamate scavengers increase pro-apoptotic signaling and reduce metastatic melanoma growth in-vivo
Abstract Inhibition of extracellular glutamate (Glu) release decreases proliferation and invasion, induces apoptosis, and inhibits melanoma metastatic abilities. Previous studies have shown that Blood-glutamate scavenging (BGS), a novel treatment approach, has been found to be beneficial in attenuat...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2021-07-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-021-94183-8 |
| _version_ | 1819037424239509504 |
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| author | Yona Goldshmit Rita Perelroizen Alex Yakovchuk Evgeni Banyas Lior Mayo Sari David Amit Benbenishty Pablo Blinder Moshe Shalom Angela Ruban |
| author_facet | Yona Goldshmit Rita Perelroizen Alex Yakovchuk Evgeni Banyas Lior Mayo Sari David Amit Benbenishty Pablo Blinder Moshe Shalom Angela Ruban |
| author_sort | Yona Goldshmit |
| collection | DOAJ |
| description | Abstract Inhibition of extracellular glutamate (Glu) release decreases proliferation and invasion, induces apoptosis, and inhibits melanoma metastatic abilities. Previous studies have shown that Blood-glutamate scavenging (BGS), a novel treatment approach, has been found to be beneficial in attenuating glioblastoma progression by reducing brain Glu levels. Therefore, in this study we evaluated the ability of BGS treatment to inhibit brain metastatic melanoma progression in-vivo. RET melanoma cells were implanted in C56BL/6J mice to induce brain melanoma tumors followed by treatment with BGS or vehicle administered for fourteen days. Bioluminescent imaging was conducted to evaluate tumor growth, and plasma/CSF Glu levels were monitored throughout. Immunofluorescence staining of Ki67 and 53BP1 was used to analyze tumor cell proliferation and DNA double-strand breaks. In addition, we analyzed CD8, CD68, CD206, p-STAT1 and iNOS expression to evaluate alterations in tumor micro-environment and anti-tumor immune response due to treatment. Our results show that BGS treatment reduces CSF Glu concentration and consequently melanoma growth in-vivo by decreasing tumor cell proliferation and increasing pro-apoptotic signaling in C56BL/6J mice. Furthermore, BGS treatment supported CD8+ cell recruitment and CD68+ macrophage invasion. These findings suggest that BGS can be of potential therapeutic relevance in the treatment of metastatic melanoma. |
| first_indexed | 2024-12-21T08:21:12Z |
| format | Article |
| id | doaj.art-200f4725602145f4a7fbf82cf2089aa6 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-21T08:21:12Z |
| publishDate | 2021-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-200f4725602145f4a7fbf82cf2089aa62022-12-21T19:10:26ZengNature PortfolioScientific Reports2045-23222021-07-0111111510.1038/s41598-021-94183-8Blood glutamate scavengers increase pro-apoptotic signaling and reduce metastatic melanoma growth in-vivoYona Goldshmit0Rita Perelroizen1Alex Yakovchuk2Evgeni Banyas3Lior Mayo4Sari David5Amit Benbenishty6Pablo Blinder7Moshe Shalom8Angela Ruban9Steyer School of Health Professions, Sackler Faculty of Medicine, Tel-Aviv UniversityShmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv UniversitySteyer School of Health Professions, Sackler Faculty of Medicine, Tel-Aviv UniversitySteyer School of Health Professions, Sackler Faculty of Medicine, Tel-Aviv UniversityShmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv UniversitySteyer School of Health Professions, Sackler Faculty of Medicine, Tel-Aviv UniversityDepartment of Biological Regulation, Weizmann Institute of ScienceSagol School of Neuroscience, Tel Aviv UniversitySteyer School of Health Professions, Sackler Faculty of Medicine, Tel-Aviv UniversitySteyer School of Health Professions, Sackler Faculty of Medicine, Tel-Aviv UniversityAbstract Inhibition of extracellular glutamate (Glu) release decreases proliferation and invasion, induces apoptosis, and inhibits melanoma metastatic abilities. Previous studies have shown that Blood-glutamate scavenging (BGS), a novel treatment approach, has been found to be beneficial in attenuating glioblastoma progression by reducing brain Glu levels. Therefore, in this study we evaluated the ability of BGS treatment to inhibit brain metastatic melanoma progression in-vivo. RET melanoma cells were implanted in C56BL/6J mice to induce brain melanoma tumors followed by treatment with BGS or vehicle administered for fourteen days. Bioluminescent imaging was conducted to evaluate tumor growth, and plasma/CSF Glu levels were monitored throughout. Immunofluorescence staining of Ki67 and 53BP1 was used to analyze tumor cell proliferation and DNA double-strand breaks. In addition, we analyzed CD8, CD68, CD206, p-STAT1 and iNOS expression to evaluate alterations in tumor micro-environment and anti-tumor immune response due to treatment. Our results show that BGS treatment reduces CSF Glu concentration and consequently melanoma growth in-vivo by decreasing tumor cell proliferation and increasing pro-apoptotic signaling in C56BL/6J mice. Furthermore, BGS treatment supported CD8+ cell recruitment and CD68+ macrophage invasion. These findings suggest that BGS can be of potential therapeutic relevance in the treatment of metastatic melanoma.https://doi.org/10.1038/s41598-021-94183-8 |
| spellingShingle | Yona Goldshmit Rita Perelroizen Alex Yakovchuk Evgeni Banyas Lior Mayo Sari David Amit Benbenishty Pablo Blinder Moshe Shalom Angela Ruban Blood glutamate scavengers increase pro-apoptotic signaling and reduce metastatic melanoma growth in-vivo Scientific Reports |
| title | Blood glutamate scavengers increase pro-apoptotic signaling and reduce metastatic melanoma growth in-vivo |
| title_full | Blood glutamate scavengers increase pro-apoptotic signaling and reduce metastatic melanoma growth in-vivo |
| title_fullStr | Blood glutamate scavengers increase pro-apoptotic signaling and reduce metastatic melanoma growth in-vivo |
| title_full_unstemmed | Blood glutamate scavengers increase pro-apoptotic signaling and reduce metastatic melanoma growth in-vivo |
| title_short | Blood glutamate scavengers increase pro-apoptotic signaling and reduce metastatic melanoma growth in-vivo |
| title_sort | blood glutamate scavengers increase pro apoptotic signaling and reduce metastatic melanoma growth in vivo |
| url | https://doi.org/10.1038/s41598-021-94183-8 |
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