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BS148 Reduces the Aggressiveness of Metastatic Melanoma via Sigma-2 Receptor Targeting
The management of advanced-stage melanoma is clinically challenging, mainly because of its resistance to the currently available therapies. Therefore, it is important to develop alternative therapeutic strategies. The sigma-2 receptor (S2R) is overexpressed in proliferating tumor cells and represent...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10253401/ https://www.ncbi.nlm.nih.gov/pubmed/37298633 http://dx.doi.org/10.3390/ijms24119684 |
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author | Sorbi, Claudia Belluti, Silvia Atene, Claudio Giacinto Marocchi, Federica Linciano, Pasquale Roy, Neena Paradiso, Elia Casarini, Livio Ronsisvalle, Simone Zanocco-Marani, Tommaso Brasili, Livio Lanfrancone, Luisa Imbriano, Carol Di Rocco, Giulia Franchini, Silvia |
author_facet | Sorbi, Claudia Belluti, Silvia Atene, Claudio Giacinto Marocchi, Federica Linciano, Pasquale Roy, Neena Paradiso, Elia Casarini, Livio Ronsisvalle, Simone Zanocco-Marani, Tommaso Brasili, Livio Lanfrancone, Luisa Imbriano, Carol Di Rocco, Giulia Franchini, Silvia |
author_sort | Sorbi, Claudia |
collection | PubMed |
description | The management of advanced-stage melanoma is clinically challenging, mainly because of its resistance to the currently available therapies. Therefore, it is important to develop alternative therapeutic strategies. The sigma-2 receptor (S2R) is overexpressed in proliferating tumor cells and represents a promising vulnerability to target. Indeed, we have recently identified a potent S2R modulator (BS148) that is effective in melanoma. To elucidate its mechanism of action, we designed and synthesized a BS148 fluorescent probe that enters SK-MEL-2 melanoma cells as assessed using confocal microscopy analysis. We show that S2R knockdown significantly reduces the anti-proliferative effect induced by BS148 administration, indicating the engagement of S2R in BS148-mediated cytotoxicity. Interestingly, BS148 treatment showed similar molecular effects to S2R RNA interference-mediated knockdown. We demonstrate that BS148 administration activates the endoplasmic reticulum stress response through the upregulation of protein kinase R-like ER kinase (PERK), activating transcription factor 4 (ATF4) genes, and C/EBP homologous protein (CHOP). Furthermore, we show that BS148 treatment downregulates genes related to the cholesterol pathway and activates the MAPK signaling pathway. Finally, we translate our results into patient-derived xenograft (PDX) cells, proving that BS148 treatment reduces melanoma cell viability and migration. These results demonstrate that BS148 is able to inhibit metastatic melanoma cell proliferation and migration through its interaction with the S2R and confirm its role as a promising target to treat cancer. |
format | Online Article Text |
id | pubmed-10253401 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-102534012023-06-10 BS148 Reduces the Aggressiveness of Metastatic Melanoma via Sigma-2 Receptor Targeting Sorbi, Claudia Belluti, Silvia Atene, Claudio Giacinto Marocchi, Federica Linciano, Pasquale Roy, Neena Paradiso, Elia Casarini, Livio Ronsisvalle, Simone Zanocco-Marani, Tommaso Brasili, Livio Lanfrancone, Luisa Imbriano, Carol Di Rocco, Giulia Franchini, Silvia Int J Mol Sci Article The management of advanced-stage melanoma is clinically challenging, mainly because of its resistance to the currently available therapies. Therefore, it is important to develop alternative therapeutic strategies. The sigma-2 receptor (S2R) is overexpressed in proliferating tumor cells and represents a promising vulnerability to target. Indeed, we have recently identified a potent S2R modulator (BS148) that is effective in melanoma. To elucidate its mechanism of action, we designed and synthesized a BS148 fluorescent probe that enters SK-MEL-2 melanoma cells as assessed using confocal microscopy analysis. We show that S2R knockdown significantly reduces the anti-proliferative effect induced by BS148 administration, indicating the engagement of S2R in BS148-mediated cytotoxicity. Interestingly, BS148 treatment showed similar molecular effects to S2R RNA interference-mediated knockdown. We demonstrate that BS148 administration activates the endoplasmic reticulum stress response through the upregulation of protein kinase R-like ER kinase (PERK), activating transcription factor 4 (ATF4) genes, and C/EBP homologous protein (CHOP). Furthermore, we show that BS148 treatment downregulates genes related to the cholesterol pathway and activates the MAPK signaling pathway. Finally, we translate our results into patient-derived xenograft (PDX) cells, proving that BS148 treatment reduces melanoma cell viability and migration. These results demonstrate that BS148 is able to inhibit metastatic melanoma cell proliferation and migration through its interaction with the S2R and confirm its role as a promising target to treat cancer. MDPI 2023-06-02 /pmc/articles/PMC10253401/ /pubmed/37298633 http://dx.doi.org/10.3390/ijms24119684 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Sorbi, Claudia Belluti, Silvia Atene, Claudio Giacinto Marocchi, Federica Linciano, Pasquale Roy, Neena Paradiso, Elia Casarini, Livio Ronsisvalle, Simone Zanocco-Marani, Tommaso Brasili, Livio Lanfrancone, Luisa Imbriano, Carol Di Rocco, Giulia Franchini, Silvia BS148 Reduces the Aggressiveness of Metastatic Melanoma via Sigma-2 Receptor Targeting |
title | BS148 Reduces the Aggressiveness of Metastatic Melanoma via Sigma-2 Receptor Targeting |
title_full | BS148 Reduces the Aggressiveness of Metastatic Melanoma via Sigma-2 Receptor Targeting |
title_fullStr | BS148 Reduces the Aggressiveness of Metastatic Melanoma via Sigma-2 Receptor Targeting |
title_full_unstemmed | BS148 Reduces the Aggressiveness of Metastatic Melanoma via Sigma-2 Receptor Targeting |
title_short | BS148 Reduces the Aggressiveness of Metastatic Melanoma via Sigma-2 Receptor Targeting |
title_sort | bs148 reduces the aggressiveness of metastatic melanoma via sigma-2 receptor targeting |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10253401/ https://www.ncbi.nlm.nih.gov/pubmed/37298633 http://dx.doi.org/10.3390/ijms24119684 |
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