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The Evolution of the Sigma-2 (σ2) Receptor from Obscure Binding Site to Bona Fide Therapeutic Target

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Book cover Sigma Receptors: Their Role in Disease and as Therapeutic Targets

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 964))

Abstract

The sigma-2 (σ2) receptor represents one of the most poorly understood proteins in cell biology. Although this receptor was identified through in vitro binding studies over 25 years ago, the molecular identity of this protein is currently not unambiguously known, and the results from recent attempts to identify the σ2 receptor through protein purification and mass spectral analysis have been the subject of debate in the literature. However, there is overwhelming data demonstrating that the σ2 receptor is an important biomarker of tumor cell proliferation . The observation that σ2 receptor agonists are potent anticancer agents whereas σ2 antagonists block Aβ1-42 oligomer synaptic dysfunction in transgenic mouse models of Alzheimer’s disease have clearly identified this protein as an important therapeutic target for the treatment of a variety of pathological conditions.

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References

  1. Walker JM et al (1990) Sigma receptors: biology and function. Pharmacol Rev 42(4):355–402

    CAS  PubMed  Google Scholar 

  2. Hellewell SB, Bowen WD (1990) A sigma-like binding site in rat pheochromocytoma (PC12) cells: decreased affinity for (+)-benzomorphans and lower molecular weight suggest a different sigma receptor form from that of guinea pig brain. Brain Res 527(2):244–253

    Article  CAS  PubMed  Google Scholar 

  3. Hellewell SB et al (1994) Rat liver and kidney contain high densities of sigma-1 and sigma-2 receptors: characterization by ligand binding and photoaffinity labeling. Eur J Pharmacol 268(1):9–18

    Article  CAS  PubMed  Google Scholar 

  4. Colabufo NA et al (2006) Is the σ2 receptor a histone binding protein? J Med Chem 49(14):4153–4158

    Article  CAS  PubMed  Google Scholar 

  5. Abate C et al (2010) Interaction of the σ2 receptor ligand PB28 with the human nucleosome: computational and experimental probes of interaction with the H2A/H2B dimer. ChemMedChem 5(2):268–273

    Article  CAS  PubMed  Google Scholar 

  6. Berardi F et al (2004) 4-(tetralin-1-yl)- and 4-(naphthalen-1-yl)alkyl derivatives of 1-cyclohexylpiperazine as sigma receptor ligands with agonist sigma-2 activity. J Med Chem 47(9):2308–2317

    Article  CAS  PubMed  Google Scholar 

  7. Azzariti A et al (2006) Cyclohexylpiperazine derivative PB28, a sigma-2 agonist and sigma-1 antagonist receptor, inhibits cell growth, modulates P-glycoprotein, and synergizes with anthracyclines in breast cancer. Mol Cancer Ther 5(7):1807–1816

    Article  CAS  PubMed  Google Scholar 

  8. Xu J et al (2011) Identification of the PGRMC1 protein complex as the putative sigma-2 receptor binding site. Nat Commun 2:380

    Article  PubMed  PubMed Central  Google Scholar 

  9. Cahill MA (2007) Progesterone receptor membrane component 1: an integrative review. J Steroid Biochem Mol Biol 105(1–5):16–36

    Article  CAS  PubMed  Google Scholar 

  10. Abate C et al (2015) Elements in support of the ‘non-identity’ of the PGRMC1 protein with the sigma2 receptor. Eur J Pharmacol 758:16–23

    Article  CAS  PubMed  Google Scholar 

  11. Chu UB et al (2015) The Sigma-2 receptor and progesterone receptor membrane component 1 are different binding sites derived from independent genes. EBioMedicine 2(11):1806–1813

    Article  PubMed  PubMed Central  Google Scholar 

  12. Vilner BJ, John CS, Bowen WD (1995) Sigma-1 and sigma-2 receptors are expressed in a wide variety of human and rodent tumor cell lines. Cancer Res 55(2):408–413

    CAS  PubMed  Google Scholar 

  13. Bem WT et al (1991) Overexpression of sigma receptors in nonneural human tumors. Cancer Res 51(24):6558–6562

    CAS  PubMed  Google Scholar 

  14. Colabufo NA et al (2006) Correlation between sigma2 receptor protein expression and histopathologic grade in human bladder cancer. Cancer Lett 237(1):83–88

    Article  CAS  PubMed  Google Scholar 

  15. Roperto S et al (2010) Sigma-2 receptor expression in bovine papillomavirus-associated urinary bladder tumours. J Comp Pathol 142(1):19–26

    Article  CAS  PubMed  Google Scholar 

  16. Mach RH et al (1997) Sigma 2 receptors as potential biomarkers of proliferation in breast cancer. Cancer Res 57(1):156–161

    CAS  PubMed  Google Scholar 

  17. Wheeler KT et al (2000) Sigma-2 receptors as a biomarker of proliferation in solid tumours. Br J Cancer 82(6):1223–1232

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Mach RH, Zeng C, Hawkins WG (2013) The sigma2 receptor: a novel protein for the imaging and treatment of cancer. J Med Chem 56(18):7137–7160

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Crawford KW, Bowen WD (2002) Sigma-2 receptor agonists activate a novel apoptotic pathway and potentiate antineoplastic drugs in breast tumor cell lines. Cancer Res 62(1):313–322

    CAS  PubMed  Google Scholar 

  20. Vilner BJ, Bowen WD (2000) Modulation of cellular calcium by sigma-2 receptors: release from intracellular stores in human SK-N-SH neuroblastoma cells. J Pharmacol Exp Ther 292(3):900–911

    CAS  PubMed  Google Scholar 

  21. Nicholson H et al (2015) Characterization of CM572, a selective irreversible partial agonist of the Sigma-2 receptor with antitumor activity. J Pharmacol Exp Ther 354(2):203–212

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Crawford KW, Coop A, Bowen WD (2002) Sigma(2) Receptors regulate changes in sphingolipid levels in breast tumor cells. Eur J Pharmacol 443(1–3):207–209

    Article  CAS  PubMed  Google Scholar 

  23. Mach RH et al (2001) Synthesis and sigma receptor binding affinities of 8-azabicyclo[3.2.1]octan-3 alpha-yl and 9-azabicyclo[3.3.1]nonan-3 alpha-yl phenylcarbamates. Med Chem Res 10(6):339–355

    CAS  Google Scholar 

  24. Mach RH et al (2004) Conformationally-flexible benzamide analogues as dopamine D3 and sigma 2 receptor ligands. Bioorg Med Chem Lett 14(1):195–202

    Article  CAS  PubMed  Google Scholar 

  25. Zeng C et al (2012) Sigma-2 ligands induce tumour cell death by multiple signalling pathways. Br J Cancer 106(4):693–701

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Zeng C et al (2014) Functional assays to define agonists and antagonists of the sigma-2 receptor. Anal Biochem 448:68–74

    Article  CAS  PubMed  Google Scholar 

  27. Hornick JR et al (2012) Lysosomal membrane permeabilization is an early event in Sigma-2 receptor ligand mediated cell death in pancreatic cancer. J Exp Clin Cancer Res 31:41

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hornick JR et al (2010) The novel sigma-2 receptor ligand SW43 stabilizes pancreas cancer progression in combination with gemcitabine. Mol Cancer 9:298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zeng C et al (2011) Characterization and evaluation of two novel fluorescent sigma-2 receptor ligands as proliferation probes. Mol Imaging 10(6):420–433

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Ostenfeld MS et al (2005) Effective tumor cell death by sigma-2 receptor ligand siramesine involves lysosomal leakage and oxidative stress. Cancer Res 65(19):8975–8983

    Article  CAS  PubMed  Google Scholar 

  31. Ostenfeld MS et al (2008) Anti-cancer agent siramesine is a lysosomotropic detergent that induces cytoprotective autophagosome accumulation. Autophagy 4(4):487–499

    Article  CAS  PubMed  Google Scholar 

  32. Cesen MH et al (2013) Siramesine triggers cell death through destabilisation of mitochondria, but not lysosomes. Cell Death Dis 4:e818

    Article  PubMed  Google Scholar 

  33. Abate C et al (2011) Fluorescent derivatives of sigma receptor ligand 1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine (PB28) as a tool for uptake and cellular localization studies in pancreatic tumor cells. J Med Chem 54(16):5858–5867

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Abate C et al (2011) Analogues of sigma receptor ligand 1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine (PB28) with added polar functionality and reduced lipophilicity for potential use as positron emission tomography radiotracers. J Med Chem 54(4):1022–1032

    Article  CAS  PubMed  Google Scholar 

  35. Kashiwagi H et al (2007) TAT-Bim induces extensive apoptosis in cancer cells. Ann Surg Oncol 14(5):1763–1771

    Article  PubMed  Google Scholar 

  36. Vilner BJ, de Costa BR, Bowen WD (1995) Cytotoxic effects of sigma ligands: sigma receptor-mediated alterations in cellular morphology and viability. J Neurosci 15(1 Pt 1):117–134

    CAS  PubMed  Google Scholar 

  37. Zeng C et al (2007) Subcellular localization of sigma-2 receptors in breast cancer cells using two-photon and confocal microscopy. Cancer Res 67(14):6708–6716

    Article  CAS  PubMed  Google Scholar 

  38. Spitzer D et al (2012) Use of multifunctional sigma-2 receptor ligand conjugates to trigger cancer-selective cell death signaling. Cancer Res 72(1):201–209

    Article  CAS  PubMed  Google Scholar 

  39. Simon PO Jr et al (2009) Targeting AKT with the proapoptotic peptide, TAT-CTMP: a novel strategy for the treatment of human pancreatic adenocarcinoma. Int J Cancer 125(4):942–951

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Du C et al (2000) Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell 102(1):33–42

    Article  CAS  PubMed  Google Scholar 

  41. Garg G et al (2014) Conjugation to a SMAC mimetic potentiates sigma-2 ligand induced tumor cell death in ovarian cancer. Mol Cancer 13(1):50

    Article  PubMed  PubMed Central  Google Scholar 

  42. Hashim, Y.M., et al., Targeted pancreatic cancer therapy with the small molecule drug conjugate SW IV-134. Mol Oncol, 8:956 2014.

    Google Scholar 

  43. Makvandi M et al (2015) The sigma-2 receptor as a therapeutic target for drug delivery in triple negative breast cancer. Biochem Biophys Res Commun 467(4):1070–1075

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Zeng C et al (2013) Sigma-2 receptor ligand as a novel method for delivering a SMAC mimetic drug for treating ovarian cancer. Br J Cancer 109(9):2368–2377

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Makvandi M et al (2016) The pre-clinical characterization of an alpha-emitting sigma-2 receptor targeted radiotherapeutic. Nucl Med Biol 43(1):35–41

    Article  CAS  PubMed  Google Scholar 

  46. Sun T et al (2014) Using SV119-gold nanocage conjugates to eradicate cancer stem cells through a combination of photothermal and chemo therapies. Adv Healthc Mater 3(8):1283–1291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Wang Y et al (2012) SV119-gold nanocage conjugates: a new platform for targeting cancer cells via sigma-2 receptors. Nanoscale 4(2):421–424

    Article  CAS  PubMed  Google Scholar 

  48. Zhang Y et al (2012) Incorporation of a selective sigma-2 receptor ligand enhances uptake of liposomes by multiple cancer cells. Int J Nanomedicine 7:4473–4485

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Kashiwagi H et al (2009) Sigma-2 receptor ligands potentiate conventional chemotherapies and improve survival in models of pancreatic adenocarcinoma. J Transl Med 7:24

    Article  PubMed  PubMed Central  Google Scholar 

  50. Guo L, Zhen X (2015) Sigma-2 receptor ligands: neurobiological effects. Curr Med Chem 22(8):989–1003

    Article  CAS  PubMed  Google Scholar 

  51. Izzo NJ et al (2014) Alzheimer’s therapeutics targeting amyloid beta 1-42 oligomers I: Abeta 42 oligomer binding to specific neuronal receptors is displaced by drug candidates that improve cognitive deficits. PLoS One 9(11):e111898

    Article  PubMed  PubMed Central  Google Scholar 

  52. Izzo NJ et al (2014) Alzheimer’s therapeutics targeting amyloid beta 1-42 oligomers II: Sigma-2/PGRMC1 receptors mediate Abeta 42 oligomer binding and synaptotoxicity. PLoS One 9(11), e111899

    Google Scholar 

  53. Iniguez MA et al (2013) Inhibitory effects of sigma-2 receptor agonists on T lymphocyte activation. Front Pharmacol 4:23

    Article  PubMed  PubMed Central  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Radiology, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Chenbo Zeng & Robert H. Mach

Authors
  1. Chenbo Zeng
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  2. Robert H. Mach
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Editor information

Editors and Affiliations

  1. Departments of Cellular Biology and Anatomy and Ophthalmology and the James and Jean Culver Vision Discovery Institute, Medical College of Georgia at Augusta University, Augusta, Georgia, USA

    Sylvia B. Smith

  2. Cellular Pathobiology Section, Integrative Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, US Department of Health and Human Services, Baltimore, Maryland, USA

    Tsung-Ping Su

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Zeng, C., Mach, R.H. (2017). The Evolution of the Sigma-2 (σ2) Receptor from Obscure Binding Site to Bona Fide Therapeutic Target. In: Smith, S., Su, TP. (eds) Sigma Receptors: Their Role in Disease and as Therapeutic Targets. Advances in Experimental Medicine and Biology, vol 964. Springer, Cham. https://doi.org/10.1007/978-3-319-50174-1_5

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