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TMEM97 and PGRMC1 do not mediate sigma-2 ligand-induced cell death
Abstract
Sigma-2 receptors have been implicated in both tumor proliferation and neurodegenerative diseases. Recently the sigma-2 receptor was identified as transmembrane protein 97 (TMEM97). Progesterone receptor membrane component 1 (PGRMC1) was also recently reported to form a complex with TMEM97 and the low density lipoprotein (LDL) receptor, and this trimeric complex is responsible for the rapid internalization of LDL. Sigma-2 receptor ligands with various structures have been shown to induce cell death in cancer cells. In the current study, we examined the role of TMEM97 and PGRMC1 in mediating sigma-2 ligand-induced cell death. Cell viability and caspase-3 assays were performed in control, TMEM97 knockout (KO), PGRMC1 KO, and TMEM97/PGRMC1 double KO cell lines treated with several sigma-2 ligands. The data showed that knockout of TMEM97, PGRMC1, or both did not affect the concentrations of sigma-2 ligands that induced 50% of cell death (EC 50), suggesting that cytotoxic effects of these compounds are not mediated by TMEM97 or PGRMC1. Sigma-1 receptor ligands, (+)-pentazocine and NE-100, did not block sigma-2 ligand cytotoxicity, suggesting that sigma-1 receptor was not responsible for sigma-2 ligand cytotoxicity. We also examined whether the alternative, residual binding site (RBS) of 1,3-Di-o-tolylguanidine (DTG) could be responsible for sigma-2 ligand cytotoxicity. Our data showed that the binding affinities (Ki) of sigma-2 ligands on the DTG RBS did not correlate with the cytotoxicity potency (EC 50) of these ligands, suggesting that the DTG RBS was not fully responsible for sigma-2 ligand cytotoxicity. In addition, we showed that knocking out TMEM97, PGRMC1, or both reduced the initial internalization rate of a sigma-2 fluorescent ligand, SW120. However, concentrations of internalized SW120 became identical later in the control and knockout cells. These data suggest that the initial internalization process of sigma-2 ligands does not appear to mediate the cell-killing effect of sigma-2 ligands. In summary, we have provided evidence that sigma-2 receptor/TMEM97 and PGRMC1 do not mediate sigma-2 ligand cytotoxicity. Our work will facilitate elucidating mechanisms of sigma-2 ligand cytotoxicity.
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TMEM97 is believed to be a key player of cholesterol homeostasis.
“TMEM97, initially known as MAC30 [47], is overexpressed in some cancers and it is believed to be a key player of cholesterol homeostasis [78] and calcium regulation [8, 74, 77].”
From Transmembrane protein 97 is a potential synaptic amyloid beta receptor in human Alzheimer’s disease (2024) · cites this paper as [78]
The TMEM97 KO, PGRMC1 KO, and DKO HeLa cell lines had complete ablation of TMEM97 and/or PGRMC1.
“previous studies characterized these cell lines and western blot data demonstrated a complete ablation of TMEM97 and/or PGRMC1 in the knockout cells [8, 39].”
From The Sigma-2 Receptor/TMEM97, PGRMC1, and LDL Receptor Complex Are Responsible for the Cellular Uptake of Aβ42 and Its Protein Aggregates (2020) · cites this paper as [39]
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Riad, A., Lengyel-Zhand, Z., Zeng, C., Weng, C.-C., Lee, V. M.-Y., Trojanowski, J. Q., & Mach, R. H. (2020) · Molecular Neurobiology · doi:10.1007/s12035-020-01988-1 · Cited by 81
Self-citationLizama, B. N., Kahle, J., Catalano, S. M., Caggiano, A. O., Grundman, M., & Hamby, M. E. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24076251 · Cited by 54
Transmembrane protein 97 is a potential synaptic amyloid beta receptor in human Alzheimer’s disease
Colom-Cadena, M., Toombs, J., Simzer, E., Holt, K., McGeachan, R., Tulloch, J., Jackson, R. J., Catterson, J. H., Spires-Jones, M. P., Rose, J., et al. (2024) · Acta Neuropathologica · doi:10.1007/s00401-023-02679-6 · Cited by 44
Metadata
- Authors
- Zeng, C., Weng, C.-C., Schneider, M. E., Puentes, L., Riad, A., Xu, K., Makvandi, M., Jin, L., Hawkins, W. G., & Mach, R. H.
- Venue
- Cell Death Discovery
- Published
- 2019-01-28
- Volume
- 5
- Issue
- 1
- ISSN
- 2058-7716
- PMC
- PMC6349905
- Cited by
- 48
- References
- 4
- Language
- en
- Funders
- Department of Radiology, University of Pennsylvania
- T32 training grant
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