Direct interaction of the sigma-1 (σ1) receptor, an endoplasmic reticulum chaperone located in close vicinity to the mitochondrion, with a variety of proteins involved in essential processes regulating proliferation, survival, and death of cells, indicates a role of this protein in tumor biology. Since tumor therapies address precisely these processes to stop the growth of tumor cells, the σ1 receptor could be a suitable modulator of the effectiveness of selected therapies. Recent initial studies have shown not only anti-proliferative effects of ligands targeting this protein, but also modulating effects in both chemotherapy and radiotherapy. However, in this regard the influence of functional expression of the σ1receptor has not yet been fully clarified. The purpose of this pilot experiment was to investigate the role of σ1 receptor on cellular radiosensitivity in an in vitro model. Therefore, clonogenic assays were performed to assess the susceptibility of HEK293 cells, stably transfected with human σ1 receptor, towards irradiation (X-ray) in comparison to non-transfected cells. Moreover, irradiation combined with pharmacological treatment should prove whether agonistic and antagonistic ligand binding to σ1 receptor influences the effectiveness of radiation treatment. The data obtained are not fully conclusive by indicating, on the one hand, an involvement of σ1 receptor in radiation-induced effects along with pharmacological effects independent from the σ1 receptor level, on the other hand, suggesting limitations of the model used herein. Consequently, subsequent work will focus on the investigation of tumor cells with different receptor densities.
AlexanderSP, KellyE, MathieA, PetersJA, VealeEL, ArmstrongJF, FaccendaE, HardingSD, PawsonAJ, SharmanJL, SouthanC, BunemanOP, CidlowskiJA, ChristopoulosA, DavenportAP, FabbroD, SpeddingM, StriessnigJ, DaviesJA, Collaborators C. THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Introduction and Other Protein Targets. British Journal of Pharmacology. 2019;176(S1):S1–S20.
3.
HayashiT, SuTP. Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival. Cell. 2007;131(3):596–610.
4.
GiorgiC, De StefaniD, BononiA, RizzutoR, PintonP. Structural and functional link between the mitochondrial network and the endoplasmic reticulum. The International Journal of Biochemistry & Cell Biology. 2009;41(10):1817–27.
5.
SchmidtHR, KruseAC. The Molecular Function of σ Receptors: Past, Present, and Future. Trends in Pharmacological Sciences. 2019;40(9):636–654.
6.
OyerHM, SandersCM, KimFJ. Small-Molecule Modulators of Sigma1 and Sigma2/TMEM97 in the Context of Cancer: Foundational Concepts and Emerging Themes. Frontiers in Pharmacology. 2019;10(1141).
7.
MaherCM, ThomasJD, HaasDA, LongenCG, OyerHM, TongJY, KimFJ. Small-Molecule Sigma1 Modulator Induces Autophagic Degradation of PD-L1. Molecular Cancer Research. 2018;16(2):243–255.
8.
ThomasJD, LongenCG, OyerHM, ChenN, MaherCM, SalvinoJM, KaniaB, AndersonKN, OstranderWF, KnudsenKE, KimFJ. Sigma1 targeting to suppress aberrant androgen receptor signaling in prostate cancer. Cancer research. 2017;77(9):2439–2452.
9.
LonghitanoL, CastracaniCC, TibulloD, AvolaR, ViolaM, RussoG, PrezzaventoO, MarrazzoA, AmataE, ReibaldiM, LongoA, RussoA, ParrinelloNL, Li VoltiG. Sigma-1 and Sigma-2 receptor ligands induce apoptosis and autophagy but have opposite effect on cell proliferation in uveal melanoma. Oncotarget. 2017;8(53):91099–91111.
10.
SpruceBA, CampbellLA, McTavishN, CooperMA, AppleyardMVL, O’NeillM, HowieJ, SamsonJ, WattS, MurrayK, McLeanD, LeslieNR, SafranyST, FergusonMJ, PetersJA, PrescottAR, BoxG, HayesA, NutleyB, RaynaudF, DownesCP, LambertJJ, ThompsonAM, EcclesS. Small Molecule Antagonists of the σ-1 Receptor Cause Selective Release of the Death Program in Tumor and Self-Reliant Cells and Inhibit Tumor Growth in Vitro and in Vivo. Cancer research. 2004;64(14):4875–4886.
11.
KroemerG, JäätteläM. Lysosomes and autophagy in cell death control. Nature Reviews Cancer. 2005;5(11):886–897.
12.
FennellyC, AmaravadiRK. Lysosomal biology in cancer. In Methods in Molecular Biology. 2017;1594:293–308.
13.
JohannessenTC, Hasan-OliveMM, ZhuH, DenisovaO, GrudicA, LatifMA, SaedH, VarugheseJK, RøslandGV, YangN, SundstrømT, NordalA, TronstadKJ, WangJ, Lund-JohansenM, SimonsenA, JanjiB, WestermarckJ, BjerkvigR, PrestegardenL. Thioridazine inhibits autophagy and sensitizes glioblastoma cells to temozolomide. International Journal of Cancer. 2019;144(7):1735–1745.
14.
RenaudoA, WatryV, ChassotAA, PonzioG, EhrenfeldJ, SorianiO. Inhibition of tumor cell proliferation by σ ligands is associated with K+channel inhibition and p27kip1 accumulation. Journal of Pharmacology and Experimental Therapeutics. 2004;311(3):1105–1114.
15.
ElmaciI, AltinozMA. Targeting the cellular schizophrenia. Likely employment of the antipsychotic agent pimozide in treatment of refractory cancers and glioblastoma. Critical Reviews in Oncology/Hematology. 2018;128:96–109.
16.
StroblJS, MelkoumianZ, PetersonVA, HyltonH. The cell death response to γ-radiation in MCF-7 cells is enhanced by a neuroleptic drug, pimozide. Breast Cancer Research and Treatment. 1998;51(1):83–95.
17.
OrdysBB, LaunayS, DeightonRF, McCullochJ, WhittleIR. The role of mitochondria in glioma pathophysiology. Molecular Neurobiology. 2010;42(1):64–75.
18.
KamWW, BanatiRB. Effects of ionizing radiation on mitochondria. Free Radic Biol Med. 2013;65:607–619.
19.
XieF, BergmannR, KniessT, Deuther-ConradW, MamatC, NeuberC, LiuB, SteinbachJ, BrustP, PietzschJ, JiaH. (18)F-Labeled 1,4-Dioxa-8-azaspiro[4.5]decane Derivative: Synthesis and Biological Evaluation of a sigma1 Receptor Radioligand with Low Lipophilicity as Potent Tumor Imaging Agent. J Med Chem. 2015;58(14):5395–407.
20.
KranzM, BergmannR, KniessT, BelterB, NeuberC, CaiZ, DengG, FischerS, ZhouJ, HuangY, BrustP, Deuther-ConradW, PietzschJ. Bridging from Brain to Tumor Imaging: (S)-(–)- and (R)-(+)-[(18)F]Fluspidine for Investigation of Sigma-1 Receptors in Tumor-Bearing Mice. Molecules (Basel, Switzerland). 2018;23(3).
21.
KranzM, SattlerB, WustN, Deuther-ConradW, PattM, MeyerPM, FischerS, DonatCK, WunschB, HesseS, SteinbachJ, BrustP, SabriO. Evaluation of the Enantiomer Specific Biokinetics and Radiation Doses of [(18)F]Fluspidine-A New Tracer in Clinical Translation for Imaging of sigma(1) Receptors. Molecules (Basel, Switzerland). 2016;21(9).
22.
LudwigFA, FischerS, HouskaR, HoeppingA, Deuther-ConradW, SchepmannD, PattM, MeyerPM, HesseS, BeckerGA, ZientekFR, SteinbachJ, WunschB, SabriO, BrustP. In vitro and in vivo Human Metabolism of (S)-[(18)F]Fluspidine - A Radioligand for Imaging sigma1 Receptors With Positron Emission Tomography (PET). Front Pharmacol. 2019;10:534.
23.
RenaudoA, L’HosteS, GuizouarnH, BorgèseF, SorianiO. Cancer Cell Cycle Modulated by a Functional Coupling between Sigma-1 Receptors and Cl–Channels. Journal of Biological Chemistry. 2007;282(4):2259–2267.
24.
ChishtiAA, Baumstark-KhanC, KochK, KolanusW, FelesS, KondaB, AzharA, SpittaLF, HenschenmacherB, DiegelerS, SchmitzC, HellwegCE. Linear Energy Transfer Modulates Radiation-Induced NF-kappa B Activation and Expression of its Downstream Target Genes. Radiation research. 2018;189(4):354–370.
25.
GravesPR, DinSU, AshamallaM, AshamallaH, GilbertTSK, GravesLM. Ionizing radiation induces EphA2 S897 phosphorylation in a MEK/ERK/RSK-dependent manner. International Journal of Radiation Biology. 2017;93(9):929–936.
26.
ReissenweberB, MoschB, PietzschJ. Experimental hypoxia does not influence gene expression and protein synthesis of Eph receptors and ephrin ligands in human melanoma cells in vitro. Melanoma research. 2013;23(2):85–95.
27.
MoschB, PietzschD, PietzschJ. Irradiation affects cellular properties and Eph receptor expression in human melanoma cells. Cell adhesion & migration. 2012;6(2):113–25.
28.
RyskampDA, KorbanS, ZhemkovV, KraskovskayaN, BezprozvannyI. Neuronal Sigma-1 Receptors: Signaling Functions and Protective Roles in Neurodegenerative Diseases. Frontiers in Neuroscience. 2019;13(862).
29.
Morin-SurunMP, CollinT, Denavit-SaubiéM, BaulieuE-E, MonnetFP. Intracellular σ1receptor modulates phospholipase C and protein kinase C activities in the brainstem. Proceedings of the National Academy of Sciences. 1999;96(14):8196–8199.
30.
SchepmannD, LehmkuhlK, BruneS, WünschB. Expression of σ receptors of human urinary bladder tumor cells (RT-4 cells) and development of a competitive receptor binding assay for the determination of ligand affinity to human σ2 receptors. Journal of Pharmaceutical and Biomedical Analysis. 2011;55(5):1136–1141.
31.
BruneS, SchepmannD, LehmkuhlK, FrehlandB, WünschB. Characterization of ligand binding to the sigma(1) receptor in a human tumor cell line (RPMI 8226) and establishment of a competitive receptor binding assay. Assay and drug development technologies. 2012;10(4):365–74.
32.
ZengC, WengC-C, SchneiderME, PuentesL, RiadA, XuK, MakvandiM, JinL, HawkinsWG, MachRH. TMEM97 and PGRMC1 do not mediate sigma-2 ligand-induced cell death. Cell Death Discovery. 2019;5(1):58.
