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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
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.
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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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