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Updated: Jul 27, 2025
Experimental Metastasis Assay
Published on: August 24, 2010
BS148 Reduces the Aggressiveness of Metastatic Melanoma via Sigma-2 Receptor Targeting
Claudia Sorbi1, Silvia Belluti1, Claudio Giacinto Atene2
1Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy.
Abstract:
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.
Insights
A new drug, BS148, effectively targets the sigma-2 receptor (S2R) in melanoma cells, inhibiting proliferation and migration. This S2R modulator offers a promising new strategy for treating advanced melanoma.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Advanced-stage melanoma presents significant therapeutic challenges due to treatment resistance.
- The sigma-2 receptor (S2R) is overexpressed in proliferating tumor cells, presenting a potential therapeutic target.
Purpose of the Study:
- To elucidate the mechanism of action of a novel S2R modulator, BS148, in melanoma treatment.
- To evaluate the efficacy of BS148 in inhibiting melanoma cell proliferation and migration.
Main Methods:
- Synthesis of a BS148 fluorescent probe for cellular uptake studies using confocal microscopy.
- Assessment of S2R's role via knockdown experiments and analysis of BS148's molecular effects.
- Investigation of BS148's impact on endoplasmic reticulum stress, cholesterol pathway, and MAPK signaling.
- Validation of BS148 efficacy in patient-derived xenograft (PDX) melanoma cells.
Main Results:
- BS148 enters melanoma cells and its anti-proliferative effect is dependent on S2R engagement.
- BS148 induces endoplasmic reticulum stress by upregulating PERK, ATF4, and CHOP.
- BS148 treatment downregulates cholesterol pathway genes and activates the MAPK signaling pathway.
- BS148 reduces viability and migration in patient-derived melanoma xenografts.
Conclusions:
- BS148 inhibits metastatic melanoma proliferation and migration via S2R interaction.
- BS148 represents a promising therapeutic agent for targeting advanced melanoma.
