Sigma-1 and Sigma-2 receptor ligands induce apoptosis and autophagy but have opposite effect on cell proliferation in uveal melanoma

Longhitano, Lucia; Castracani, Carlo Castruccio; Tibullo, Daniele; Avola, Roberto; Viola, M.; Russo, Giuliano; Prezzavento, Orazio; Marrazzo, Agostino; Amata, Emanuele; Reibaldi, Michele; Longo, Antonio; Russo, Andrea; Parrinello, Nunziatina Laura; Volti, Giovanni Li

doi:10.18632/oncotarget.19556

Cited by 17 publications

(16 citation statements)

References 48 publications

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“…This demonstrates that the σ2R/TMEM97 ligand, NO1, reduced cell migration; meanwhile, SM21 has the opposite effect in migration. Altogether, these results reveal a relevant functional role σ2R/TMEM97 on triple negative MDA-MB-231 breast cancer cells which agrees with previous results obtained in other cell models, as well as with different σ2R/TMEM97 agonists [35,36].…”

Section: σ2r/tmem97 Ligands Alter Tnbc Cell Proliferation and Migrationsupporting

confidence: 91%

NO1, a New Sigma 2 Receptor/TMEM97 Fluorescent Ligand, Downregulates SOCE and Promotes Apoptosis in the Triple Negative Breast Cancer Cell Lines

Cantonero

Camello

Abate

et al. 2020

Cancers

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(1) Background: The structure of the Sigma 2 receptor/TMEM97 (σ2RTMEM97) has recently been reported. (2, 3) Methods and results: We used genetic and biochemical approaches to identify the molecular mechanism downstream of σ2R/TMEM97. The novel σ2R/TMEM97 fluorescent ligand, NO1, reduced the proliferation and survival of the triple negative breast cancer cell lines (TNBC: MDA-MB-231 and MDA-MB-468 cell lines), due to NO1-induced apoptosis. Greater bioaccumulation and faster uptake of NO1 in MDA-MB-231 cells compared to MCF10A or MCF7 cell lines were also shown. Accordingly, elevated σ2R/TMEM97 expression was confirmed by Western blotting. In contrast to NO1, other σ2R/TMEM97 ligands, such as SM21 and PB28, enhanced MDA-MB-231 cell proliferation and migration. Store-operated calcium entry (SOCE) is crucial for different cancer hallmarks. Here, we show that NO1, but not other σ2R/TMEM97 ligands, reduced SOCE in MDA-MB-231 cells. Similarly, TMEM97 silencing in MDA-MB-231 cells also impaired SOCE. NO1 administration downregulated STIM1-Orai1 interaction, probably by impairing the positive regulatory effect of σ2R/TMEM97 on STIM1, as we were unable to detect interaction with Orai1. (4) Conclusion: σ2R/TMEM97 is a key protein for the survival of triple negative breast cancer cells by promoting SOCE; therefore, NO1 may become a good pharmacological tool to avoid their proliferation.

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Section: σ2r/tmem97 Ligands Alter Tnbc Cell Proliferation and Migrationsupporting

confidence: 91%

NO1, a New Sigma 2 Receptor/TMEM97 Fluorescent Ligand, Downregulates SOCE and Promotes Apoptosis in the Triple Negative Breast Cancer Cell Lines

Cantonero

Camello

Abate

et al. 2020

Cancers

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“…However, S2R was recently cloned using a chemical biology approach and identified as TMEM97, an ER-resident transmembrane protein that regulates the sterol transporter NPC1 [144]. Although the two proteins, S1R and S2R, are not genetically related, they share similarities in their pharmacological profile and some S1R ligands also show high affinity for S2R, such as haloperidol, DTG, or fabomotizole [145][146][147][148][149]. Several S2R antagonists are shown to have beneficial effects in neurodegenerative diseases such as AD and are currently evaluated in clinical trials [150][151][152].…”

Section: Possible Mechanisms For the Bi-phasic Drug Effectmentioning

confidence: 99%

Bi-phasic dose response in the preclinical and clinical developments of sigma-1 receptor ligands for the treatment of neurodegenerative disorders

Maurice

2020

Expert Opinion on Drug Discovery

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Introduction: The sigma-1 receptor (S1R) is attracting much attention as a target for diseasemodifying therapies in neurodegenerative diseases. It is a highly conserved protein, present in plasma and endoplasmic reticulum (ER) membranes and enriched in mitochondria-associated ER membranes (MAMs). It modulates ER-mitochondria Ca 2+ transfer and activation of the ER stress pathways. Mitochondrial and MAM dysfunctions contribute to neurodegenerative processes in pathologies such as Alzheimer's disease, Parkinson's disease, Huntington's disease or Amyotrophic Lateral Sclerosis. Interestingly, the S1R can be activated by small druggable molecules and accumulating preclinical data suggest that S1R agonists are effective protectants in these neurodegenerative diseases. Area covered: In this review, we will present the data showing the high therapeutic potential of S1R drugs for the treatment of neurodegenerative diseases, focusing on pridopidine as a potent and selective S1R agonist under clinical development. Of particular interest is the biphasic (bell-shaped) dose-response effect, representing a common feature of all S1R agonists and described in numerous preclinical models in vitro, in vivo and in clinical trials. Expert opinion: S1R agonists modulate essential inter-organelles communication altered in all neurodegenerative diseases and activate numerous intracellular survival pathways. Research in the field will continue growing in the near future. The particular cellular nature of this unique chaperone protein must be better understood to facilitate the developement of promising molecules at the clinical stage.

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“…Different from HP-mII, which displays a preferential activity for σ receptors compared to other receptor systems, antiproliferation by HP on UM 92-1 cells may be due to additional nonspecific effects. 20 , 21 …”

Section: Introductionmentioning

confidence: 99%

Haloperidol Metabolite II Valproate Ester (S)-(−)-MRJF22: Preliminary Studies as a Potential Multifunctional Agent Against Uveal Melanoma

Barbaraci

Giurdanella

Leotta³

et al. 2021

J. Med. Chem.

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Increased angiogenesis and vascular endothelial growth factor (VEGF) levels contribute to higher metastasis and mortality in uveal melanoma (UM), an aggressive malignancy of the eye in adults. (±)-MRJF22 , a prodrug of the sigma (σ) ligand haloperidol metabolite II conjugated with the histone deacetylase (HDAC) inhibitor valproic acid, has previously demonstrated a promising antiangiogenic activity. Herein, the asymmetric synthesis of (R)-(+)-MRJF22 and (S)-(−)-MRJF22 was performed to investigate their contribution to (±)-MRJF22 antiangiogenic effects in human retinal endothelial cells (HREC) and to assess their therapeutic potential in primary human uveal melanoma (UM) 92-1 cell line. While both enantiomers displayed almost identical capabilities to reduce cell viability than the racemic mixture, (S)-(−)-MRJF22 exhibited the highest antimigratory effects in endothelial and tumor cells. Given the fundamental contribution of cell motility to cancer progression, (S)-(−)-MRJF22 may represent a promising candidate for novel antimetastatic therapy in patients with UM.

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Sigma-1 and Sigma-2 receptor ligands induce apoptosis and autophagy but have opposite effect on cell proliferation in uveal melanoma

Cited by 17 publications

References 48 publications

NO1, a New Sigma 2 Receptor/TMEM97 Fluorescent Ligand, Downregulates SOCE and Promotes Apoptosis in the Triple Negative Breast Cancer Cell Lines

NO1, a New Sigma 2 Receptor/TMEM97 Fluorescent Ligand, Downregulates SOCE and Promotes Apoptosis in the Triple Negative Breast Cancer Cell Lines

Bi-phasic dose response in the preclinical and clinical developments of sigma-1 receptor ligands for the treatment of neurodegenerative disorders

Haloperidol Metabolite II Valproate Ester (S)-(−)-MRJF22: Preliminary Studies as a Potential Multifunctional Agent Against Uveal Melanoma

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