Disease relevance of TSPO

• To explore whether PBR expression level could be of prognostic value in invasive breast cancer, we studied a series of 117 patients who underwent surgery for primary breast carcinomas and were followed-up for 8 years [1].
• RESULTS: Twenty-eight % of the colorectal cancers strongly overexpressed PBR [2].
• It has been speculated that patients with congenital lipoid adrenal hyperplasia, who cannot make any steroids, might have a genetic lesion in mBzR [3].
• Among normal breast tissues, fibroadenomas, primary and metastatic adenocarcinomas, there is a progressive increase in PBR levels parallel to the invasive and metastatic ability of the tumor (p < 0.0001) [4].
• Thus, we propose that PBR overexpression could serve as a novel prognostic indicator of an aggressive phenotype in breast, colorectal and prostate cancers [4].
• This research has generated significant efforts from multiple research groups throughout the world to apply TSPO as a marker of "active" brain pathology using in vivo imaging modalities such as Positron Emission Tomography (PET) in experimental animals and humans [5].
• These data suggest that blocking TSPO function in tumor cells induces cell death and denotes a survival role for TSPO in prostate cancer and provides the first evidence for the use of benzodiazepines in prostate cancer therapeutics [6].

Psychiatry related information on TSPO

• We evaluated an association study between two missense variations of the BZRP gene and mood disorders in a Japanese sample [7].
• Stress, anxiety disorders, and neurological disorders, as well as their treatment, can affect PBR levels in blood cells [8].
• The purpose of this study was to evaluate the PBR density on platelets from patients with generalized social phobia (GSP) [9].
• Altered platelet peripheral-type benzodiazepine receptor in posttraumatic stress disorder [10].
• Reduced platelet PBR density has been demonstrated in generalized anxiety disorder (GAD), but not in obsessive-compulsive disorder (OCD) [10].

High impact information on TSPO

• The chemotactic effects of benzodiazepine receptor agonists were blocked by the peripheral benzodiazepine receptor antagonist PK-11195, suggesting that these effects are mediated by the peripheral-type benzodiazepine receptor [11].
• Myxoma virus infection and the associated expression of early proteins, including M11L, protects cells from staurosporine- and Fas-mediated mitochondrial membrane potential loss and this effect is augmented by the presence of PBR [12].
• Close association of M11L and the PBR is also indicated by fluorescence resonance energy transfer (FRET) analysis [12].
• Many functions are associated directly or indirectly with the PBR, including the regulation of cholesterol transport and the synthesis of steroid hormones, porphyrin transport and heme synthesis, apoptosis, cell proliferation, anion transport, regulation of mitochondrial functions and immunomodulation [13].
• Based on these functions, there are many potential clinical applications of PBR modulation, such as in oncologic, endocrine, neuropsychiatric and neurodegenerative diseases [13].

Chemical compound and disease context of TSPO

• The benzodiazepine receptor (peripheral) (BZRP) plays an important role in the steroid syntheses of the adrenal glands and brain, which is possibly involved in the pathophysiology of mood disorders [7].
• High levels of peripheral-type benzodiazepine receptor (PBR), the alternative-binding site for diazepam, are part of the aggressive human breast cancer cell phenotype in vitro [4].
• Results from fluorescence microscopy showed that these probes specifically labeled the PBR at the mitochondrial level in C6 glioma cells [14].
• In the present study, we have shown that micromolar concentrations of FGIN-1-27 and Ro 5-4864, two chemically unrelated PBR ligands are toxic for both PBR-expressing SK-N-BE neuroblastoma cells and PBR-deficient Jurkat lymphoma cells [15].
• We found PBR expression in the malignant breast cancer tumors, representing various levels of estrogen and/or progesterone receptors, as well as in the MCF-7 breast carcinoma cell line [16].

Biological context of TSPO

• These results do not suggest that the BZRP gene plays a role in the genetic predisposition of affective disorders [7].
• We screened 11 patients with schizophrenia and 10 controls, which were used in a previous postmortem study, for their genomic sequences of the BZRP gene in order to find DNA sequence variations [17].
• The peripheral benzodiazepine receptor (PBR) has been known to have many functions such as a role in cell proliferation, cell differentiation, steroidogenesis, calcium flow, cellular respiration, cellular immunity, malignancy, and apoptosis [18].
• The PBR ligands did not induce cell death in hMSCs [18].
• The mBzR consists of three components; the 18-kDa component on the outer mitochondrial membrane appears to contain the benzodiazepine binding site, and is hence often termed the peripheral benzodiazepine receptor (PBR) [3].

Anatomical context of TSPO

• The benzodiazepine receptor (peripheral) (BZRP) mainly localized on glial cells plays a role in neurosteroid synthesis, and increases with glial proliferation [17].
• PURPOSE: The peripheral benzodiazepine receptor (PBR) expression has been shown dramatically increased in neoplastic tissues and tumor cell lines originated from ovary, liver, colon, breast, or brain relative to untransformed tissues [1].
• PBR-specific staining was compared in cancer tissues and normal mucosa [2].
• However, the presence of PBR has not been examined in mesenchymal stem cells [18].
• In this study, we demonstrated the expression of PBR in human bone marrow stromal cells (hBMSCs) and human adipose stromal cells (hATSCs) by RT-PCR and immunocytochemistry [18].

Associations of TSPO with chemical compounds

• We have recently reported a significant decrease in the density of BZRP labeled by [3H] PK 11195 in the postmortem brain of chronic schizophrenics, suggesting that dysfunctions of the BZRP are involved in the pathophysiology of schizophrenia [17].
• To determine the roles of PBR in cellular functions of human mesenchymal stem cells (hMSCs), effects of diazepam, PK11195, and Ro5-4864 were examined [18].
• However, clonazepam, which does not have an affinity to PBR, did not affect adipose differentiation and proliferation of hMSCs [18].
• The mitochondrial benzodiazepine receptor (mBzR) appears to be a key factor in the flow of cholesterol into mitochondria to permit the initiation of steroid hormone synthesis [3].
• Several molecules of PBR may associate to form a channel through which cholesterol passes to the inner mitochondrial membrane, and endozepine is the natural ligand for PBR [19].
• In-vivo, the proapoptotic TSPO ligand, FGIN-1-27 significantly reduced the growth rate of grafted tumors (40% less), in comparison with vehicle-treated mice [20].

Regulatory relationships of TSPO

• Possible involvement of the peripheral-type benzodiazepine receptor (PBR) in hemin/protoporphyrin-induced erythroid differentiation of human leukemia K562 cells was investigated by the use of the ligands, diazepam and PK11195 [21].

Other interactions of TSPO

• The steroidogenic acute regulatory protein (StAR) is responsible for acute control of cholesterol transport across the mitochondrial membrane, however the mechanism of StAR-associated cholesterol transport is unknown and may involve the peripheral-type benzodiazepine receptor (PBR)/endozepine system [19].
• RT-PCR and RNase protection experiments confirm that both PBR and PBR-S are expressed in all tissues examined and that expression PBR-S is about 10 times the level of PBR [3].
• Such genes include monoamine oxidase (MAO-A isoform), the peripheral-type benzodiazepine receptor and nitric oxide synthase (nNOS isoform) [22].
• The mitochondrial benzodiazepine receptor: evidence for association with the voltage-dependent anion channel (VDAC) [23].
• The article highlighted in this issue is "Reversal of Bcl-2 Mediated Resistance of the EW36 Human B-Cell Lymphoma Cell Line to Arsenite and Pesticide-Induced Apoptosis by PK11195, a Ligand of the Mitochondrial Benzodiazepine Receptor" by Donna E [24].

Analytical, diagnostic and therapeutic context of TSPO

• Although the disease-free survival was not affected by PBR in the whole population, high PBR expression level was significantly correlated with a shorter disease-free survival in the lymph node-negative patients, P = 0.038 [1].
• Using the DNA chip technology, we analyzed the PBR expression-dependent gene changes and evidenced that PBR-expressing cells exhibited more mature features than mock-transfected ones [25].
• We examined PBR levels and distribution in normal tissue and tumors from multiple cancer types by immunohistochemistry [4].
• In another series of experiments, we used semipurified Leydig cell preparations to measure StAR, PBR, P450scc, and TnNOS by Western blot analysis [26].
• Molecular cloning and chromosomal localization of a human peripheral-type benzodiazepine receptor [27].

References