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Translocator Protein (TSPO)

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (30 September 2016) | Viewed by 68399

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Prof. Dr. Nunzio Denora

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Department of Pharmacy-Pharmaceutical Sciences, University of Bari “Aldo Moro”, I-70125 Bari, Italy
Interests: drug delivery; drug targeting; TSPO; imaging; tumors
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Prof. Dr. Giovanni Natile

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Department of Chemistry, University of Bari "Aldo Moro", Via E. Orabona 4, 70125 Bari, Italy
Interests: transport of anti-tumoral platinum-based drugs and their interaction with proteins and DNA; non-classic platinum anticancer drugs; active trans-platinum compounds; platinum compounds with uncommon coordination numbers and oxidation states and activation of unsaturated ligands
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Dear Colleagues,

Decades of study on the 18-kDa mitochondrial translocator protein (TSPO), first discovered in the late 1977 as an alternative binding site for the benzodiazepine diazepam in the kidneys, have revealed that this protein participates in a variety of cellular functions, including cholesterol transport, steroid hormone synthesis, mitochondrial respiration, permeability transition pore opening, apoptosis, and cell proliferation. In accordance with TSPO's diverse functions, changes in TSPO expression have been linked to multiple diseases, from cancer to endocrine and neurological diseases. Thus, TSPO has become an extremely attractive subcellular target for: (1) the early detection of disease states that involve the overexpression of this protein; (2) selective mitochondrial drug delivery.

Investigation of the functions of this protein, both in vitro and in vivo, has been mainly carried out using high-affinity ligands, such as isoquinoline carboxamides (e.g., PK 11195) and benzodiazepines (e.g., Ro5-4864). For instance, PK 11195 and Ro5-4864 have been used to explore TSPO distribution and function in various tissues and pathologies, thus allowing for the mapping of the “peripheral binding site” in almost every tissue examined. In time, the number of structurally diverse TSPO drug ligands investigated has increased steeply, thus highlighting the great interest of the scientific community in understanding the functions of this translocator protein in both normal conditions and pathological states.

This Special Issue will consist of reviews and primary data manuscripts, and will focus on: (1) new potent and selective TSPO ligands; (2) the use of ligands as imaging tools for the early diagnosis of diseases characterized by the high expression of TSPO, such as neuroinflammation and TSPO-rich cancers; (3) TSPO targeted nanocarriers that deliver therapeutics and diagnostics; (4) TSPO ligands that could be used to prepare coordination complexes of metallodrugs, for use in diagnosis and therapy; (5) TSPO ligands as pro-apoptotic agents that are potentially useful for the treatment of cancers; and (6) in vitro and in vivo investigations of the ability of TSPO ligands to affect steroidogenesis.

Prof. Giovanni Natile
Prof. Dr. Nunzio Denora
Guest Editors

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Keywords

translocator protein (TSPO)
translocator protein 18-kDa
PBR
mitochondria
TSPO ligand
imaging
PET
microglia
neuroinflammation
Alzheimer
steroidogenesis
drug targeting
apoptosis
cancer

Related Special Issue

Translocator Protein (TSPO) in Drug Delivery and Imaging of Pathological Disorders in International Journal of Molecular Sciences (13 articles)

Published Papers (10 papers)

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Editorial

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An Updated View of Translocator Protein (TSPO)

by Nunzio Denora and Giovanni Natile

Int. J. Mol. Sci. 2017, 18(12), 2640; https://doi.org/10.3390/ijms18122640 - 06 Dec 2017

Cited by 25 | Viewed by 3851

Abstract

Decades of study on the role of mitochondria in living cells have evidenced the importance of the 18 kDa mitochondrial translocator protein (TSPO), first discovered in the 1977 as an alternative binding site for the benzodiazepine diazepam in the kidneys. This protein participates in a variety of cellular functions, including cholesterol transport, steroid hormone synthesis, mitochondrial respiration, permeability transition pore opening, apoptosis, and cell proliferation. Thus, TSPO has become an extremely attractive subcellular target for the early detection of disease states that involve the overexpression of this protein and the selective mitochondrial drug delivery. This special issue was programmed with the aim of summarizing the latest findings about the role of TSPO in eukaryotic cells and as a potential subcellular target of diagnostics or therapeutics. A total of 9 papers have been accepted for publication in this issue, in particular, 2 reviews and 7 primary data manuscripts, overall describing the main advances in this field. Full article

(This article belongs to the Special Issue Translocator Protein (TSPO))

Research

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Classical and Novel TSPO Ligands for the Mitochondrial TSPO Can Modulate Nuclear Gene Expression: Implications for Mitochondrial Retrograde Signaling

by Nasra Yasin, Leo Veenman, Sukhdev Singh, Maya Azrad, Julia Bode, Alex Vainshtein, Beatriz Caballero, Ilan Marek and Moshe Gavish

Int. J. Mol. Sci. 2017, 18(4), 786; https://doi.org/10.3390/ijms18040786 - 07 Apr 2017

Cited by 41 | Viewed by 6879

Abstract

It is known that knockdown of the mitochondrial 18 kDa translocator protein (TSPO) as well as TSPO ligands modulate various functions, including functions related to cancer. To study the ability of TSPO to regulate gene expression regarding such functions, we applied microarray analysis of gene expression to U118MG glioblastoma cells. Within 15 min, the classical TSPO ligand PK 11195 induced changes in expression of immediate early genes and transcription factors. These changes also included gene products that are part of the canonical pathway serving to modulate general gene expression. These changes are in accord with real-time, reverse transcriptase (RT) PCR. At the time points of 15, 30, 45, and 60 min, as well as 3 and 24 h of PK 11195 exposure, the functions associated with the changes in gene expression in these glioblastoma cells covered well known TSPO functions. These functions included cell viability, proliferation, differentiation, adhesion, migration, tumorigenesis, and angiogenesis. This was corroborated microscopically for cell migration, cell accumulation, adhesion, and neuronal differentiation. Changes in gene expression at 24 h of PK 11195 exposure were related to downregulation of tumorigenesis and upregulation of programmed cell death. In the vehicle treated as well as PK 11195 exposed cell cultures, our triple labeling showed intense TSPO labeling in the mitochondria but no TSPO signal in the cell nuclei. Thus, mitochondrial TSPO appears to be part of the mitochondria-to-nucleus signaling pathway for modulation of nuclear gene expression. The novel TSPO ligand 2-Cl-MGV-1 appeared to be very specific regarding modulation of gene expression of immediate early genes and transcription factors. Full article

(This article belongs to the Special Issue Translocator Protein (TSPO))

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2194 KiB

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Effect of the CRAC Peptide, VLNYYVW, on mPTP Opening in Rat Brain and Liver Mitochondria

by Tamara Azarashvili, Olga Krestinina, Yulia Baburina, Irina Odinokova, Vladimir Akatov, Igor Beletsky, John Lemasters and Vassilios Papadopoulos

Int. J. Mol. Sci. 2016, 17(12), 2096; https://doi.org/10.3390/ijms17122096 - 13 Dec 2016

Cited by 9 | Viewed by 4570

Abstract

The translocator protein (TSPO; 18 kDa) is a high-affinity cholesterol-binding protein located in the outer membrane of mitochondria. A domain in the C-terminus of TSPO was characterized as the cholesterol recognition/interaction amino acid consensus (CRAC). The ability of the CRAC domain to bind to cholesterol led us to hypothesize that this peptide may participate in the regulation of mitochondrial membrane permeability. Herein, we report the effect of the synthetic CRAC peptide, VLNYYVW, on mitochondrial permeability transition pore (mPTP) opening. It was found that the CRAC peptide alone prevents the mPTP from opening, as well as the release of apoptotic factors (cytochrome c, AIF, and EndoG) in rat brain mitochondria (RBM). Co-incubation of CRAC, together with the TSPO drug ligand, PK 11195, resulted in the acceleration of mPTP opening and in the increase of apoptotic factor release. VLNYYVW did not induce swelling in rat liver mitochondria (RLM). 3,17,19-androsten-5-triol (19-Atriol; an inhibitor of the cholesterol-binding activity of the CRAC peptide) alone and in combination with the peptide was able to stimulate RLM swelling, which was Ca²⁺- and CsA-sensitive. Additionally, a combination of 19-Atriol with 100 nM PK 11195 or with 100 µM PK 11195 displayed the opposite effect: namely, the addition of 19-Atriol with 100 µM PK 11195 in a suspension of RLM suppressed the Ca²⁺-induced swelling of RLM by 40%, while the presence of 100 nM PK 11195 with 19-Atriol enhanced the swelling of RLM by 60%. Taken together, these data suggest the participation of the TSPO’s CRAC domain in the regulation of permeability transition. Full article

(This article belongs to the Special Issue Translocator Protein (TSPO))

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Regulation of Translocator Protein 18 kDa (TSPO) Expression in Rat and Human Male Germ Cells

by Gurpreet Manku and Martine Culty

Int. J. Mol. Sci. 2016, 17(9), 1486; https://doi.org/10.3390/ijms17091486 - 06 Sep 2016

Cited by 7 | Viewed by 5380

Abstract

Translocator protein 18 kDa (TSPO) is a high affinity cholesterol- and drug-binding protein highly expressed in steroidogenic cells, such as Leydig cells, where it plays a role in cholesterol mitochondrial transport. We have previously shown that TSPO is expressed in postnatal day 3 rat gonocytes, precursors of spermatogonial stem cells. Gonocytes undergo regulated phases of proliferation and migration, followed by retinoic acid (RA)-induced differentiation. Understanding these processes is important since their disruption may lead to the formation of carcinoma in situ, a precursor of testicular germ cell tumors (TGCTs). Previously, we showed that TSPO ligands do not regulate gonocyte proliferation. In the present study, we found that TSPO expression is downregulated in differentiating gonocytes. Similarly, in F9 embryonal carcinoma cells, a mouse TGCT cell line with embryonic stem cell properties, there is a significant decrease in TSPO expression during RA-induced differentiation. Silencing TSPO expression in gonocytes increased the stimulatory effect of RA on the expression of the differentiation marker Stra8, suggesting that TSPO exerts a repressive role on differentiation. Furthermore, in normal human testes, TSPO was located not only in Leydig cells, but also in discrete spermatogenic phases such as the forming acrosome of round spermatids. By contrast, seminomas, the most common type of TGCT, presented high levels of TSPO mRNA. TSPO protein was expressed in the cytoplasmic compartment of seminoma cells, identified by their nuclear expression of the transcription factors OCT4 and AP2G. Thus, TSPO appears to be tightly regulated during germ cell differentiation, and to be deregulated in seminomas, suggesting a role in germ cell development and pathology. Full article

(This article belongs to the Special Issue Translocator Protein (TSPO))

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Synthesis and Evaluation of Tricarbonyl ^99mTc-Labeled 2-(4-Chloro)phenyl-imidazo[1,2-a]pyridine Analogs as Novel SPECT Imaging Radiotracer for TSPO-Rich Cancer

by Ji Young Choi, Rosa Maria Iacobazzi, Mara Perrone, Nicola Margiotta, Annalisa Cutrignelli, Jae Ho Jung, Do Dam Park, Byung Seok Moon, Nunzio Denora, Sang Eun Kim and Byung Chul Lee

Int. J. Mol. Sci. 2016, 17(7), 1085; https://doi.org/10.3390/ijms17071085 - 07 Jul 2016

Cited by 12 | Viewed by 5728

Abstract

The 18-kDa translocator protein (TSPO) levels are associated with brain, breast, and prostate cancer progression and have emerged as viable targets for cancer therapy and imaging. In order to develop highly selective and active ligands with a high affinity for TSPO, imidazopyridine-based TSPO ligand (CB256, 3) was prepared as the precursor. ^99mTc- and Re-CB256 (1 and 2, respectively) were synthesized in high radiochemical yield (74.5% ± 6.4%, decay-corrected, n = 5) and chemical yield (65.6%) by the incorporation of the [^99mTc(CO)₃(H₂O)₃]⁺ and (NEt₄)₂[Re(CO)₃Br₃] followed by HPLC separation. Radio-ligand 1 was shown to be stable (>99%) when incubated in human serum for 4 h at 37 °C with a relatively low lipophilicity (logD = 2.15 ± 0.02). The rhenium-185 and -187 complex 2 exhibited a moderate affinity (K_i = 159.3 ± 8.7 nM) for TSPO, whereas its cytotoxicity evaluated on TSPO-rich tumor cell lines was lower than that observed for the precursor. In vitro uptake studies of 1 in C6 and U87-MG cells for 60 min was found to be 9.84% ± 0.17% and 7.87% ± 0.23% ID, respectively. Our results indicated that ^99mTc-CB256 can be considered as a potential new TSPO-rich cancer SPECT imaging agent and provides the foundation for further in vivo evaluation. Full article

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TSPO PIGA Ligands Promote Neurosteroidogenesis and Human Astrocyte Well-Being

by Eleonora Da Pozzo, Chiara Giacomelli, Barbara Costa, Chiara Cavallini, Sabrina Taliani, Elisabetta Barresi, Federico Da Settimo and Claudia Martini

Int. J. Mol. Sci. 2016, 17(7), 1028; https://doi.org/10.3390/ijms17071028 - 29 Jun 2016

Cited by 31 | Viewed by 5469

Abstract

The steroidogenic 18 kDa translocator protein (TSPO) is an emerging, attractive therapeutic tool for several pathological conditions of the nervous system. Here, 13 high affinity TSPO ligands belonging to our previously described N,N-dialkyl-2-phenylindol-3-ylglyoxylamide (PIGA) class were evaluated for their potential ability to affect the cellular Oxidative Metabolism Activity/Proliferation index, which is used as a measure of astrocyte well-being. The most active PIGA ligands were also assessed for steroidogenic activity in terms of pregnenolone production, and the values were related to the metabolic index in rat and human models. The results showed a positive correlation between the increase in the Oxidative Metabolism Activity/Proliferation index and the pharmacologically induced stimulation of steroidogenesis. The specific involvement of steroid molecules in mediating the metabolic effects of the PIGA ligands was demonstrated using aminoglutethimide, a specific inhibitor of the first step of steroid biosynthesis. The most promising steroidogenic PIGA ligands were the 2-naphthyl derivatives that showed a long residence time to the target, in agreement with our previous data. In conclusion, TSPO ligand-induced neurosteroidogenesis was involved in astrocyte well-being. Full article

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Synthesis, Characterization, and Cytotoxicity of the First Oxaliplatin Pt(IV) Derivative Having a TSPO Ligand in the Axial Position

by Salvatore Savino, Nunzio Denora, Rosa Maria Iacobazzi, Letizia Porcelli, Amalia Azzariti, Giovanni Natile and Nicola Margiotta

Int. J. Mol. Sci. 2016, 17(7), 1010; https://doi.org/10.3390/ijms17071010 - 25 Jun 2016

Cited by 20 | Viewed by 8311

Abstract

The first Pt(IV) derivative of oxaliplatin carrying a ligand for TSPO (the 18-kDa mitochondrial translocator protein) has been developed. The expression of the translocator protein in the brain and liver of healthy humans is usually low, oppositely to steroid-synthesizing and rapidly proliferating tissues, where TSPO is much more abundant. The novel Pt(IV) complex, cis,trans,cis-[Pt(ethanedioato)Cl{2-(2-(4-(6,8-dichloro-3-(2-(dipropylamino)-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)phenoxy)acetate)-ethanolato}(1R,2R-DACH)] (DACH = diaminocyclohexane), has been fully characterized by spectroscopic and spectrometric techniques and tested in vitro against human MCF7 breast carcinoma, U87 glioblastoma, and LoVo colon adenocarcinoma cell lines. In addition, affinity for TSPO (IC₅₀ = 18.64 nM), cellular uptake (ca. 2 times greater than that of oxaliplatin in LoVo cancer cells, after 24 h treatment), and perturbation of cell cycle progression were investigated. Although the new compound was less active than oxaliplatin and did not exploit a synergistic proapoptotic effect due to the presence of the TSPO ligand, it appears to be promising in a receptor-mediated drug targeting context towards TSPO-overexpressing tumors, in particular colorectal cancer (IC₅₀ = 2.31 μM after 72 h treatment). Full article

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TSPO Ligand-Methotrexate Prodrug Conjugates: Design, Synthesis, and Biological Evaluation

by Valentino Laquintana, Nunzio Denora, Annalisa Cutrignelli, Mara Perrone, Rosa Maria Iacobazzi, Cosimo Annese, Antonio Lopalco, Angela Assunta Lopedota and Massimo Franco

Int. J. Mol. Sci. 2016, 17(6), 967; https://doi.org/10.3390/ijms17060967 - 18 Jun 2016

Cited by 9 | Viewed by 6398

Abstract

The 18-kDa translocator protein (TSPO) is a potential mitochondrial target for drug delivery to tumors overexpressing TSPO, including brain cancers, and selective TSPO ligands have been successfully used to selectively deliver drugs into the target. Methotrexate (MTX) is an anticancer drug of choice for the treatment of several cancers, but its permeability through the blood brain barrier (BBB) is poor, making it unsuitable for the treatment of brain tumors. Therefore, in this study, MTX was selected to achieve two TSPO ligand-MTX conjugates (TSPO ligand α-MTX and TSPO ligand γ-MTX), potentially useful for the treatment of TSPO-rich cancers, including brain tumors. In this work, we have presented the synthesis, the physicochemical characterizations, as well as the in vitro stabilities of the new TSPO ligand-MTX conjugates. The binding affinity for TSPO and the selectivity versus central-type benzodiazepine receptor (CBR) was also investigated. The cytotoxicity of prepared conjugates was evaluated on MTX-sensitive human and rat glioma cell lines overexpressing TSPO. The estimated coefficients of lipophilicity and the stability studies of the conjugates confirm that the synthesized molecules are stable enough in buffer solution at pH 7.4, as well in physiological medium, and show an increased lipophilicity compared to the MTX, compatible with a likely ability to cross the blood brain barrier. The latter feature of two TSPO ligand-MTX conjugates was also confirmed by in vitro permeability studies conducted on Madin-Darby canine kidney cells transfected with the human MDR1 gene (MDCK-MDR1) monolayers. TSPO ligand-MTX conjugates have shown to possess a high binding affinity for TSPO, with IC₅₀ values ranging from 7.2 to 40.3 nM, and exhibited marked toxicity against glioma cells overexpressing TSPO, in comparison with the parent drug MTX. Full article

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Review

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Tetrapyrroles as Endogenous TSPO Ligands in Eukaryotes and Prokaryotes: Comparisons with Synthetic Ligands

by Leo Veenman, Alex Vainshtein, Nasra Yasin, Maya Azrad and Moshe Gavish

Int. J. Mol. Sci. 2016, 17(6), 880; https://doi.org/10.3390/ijms17060880 - 04 Jun 2016

Cited by 38 | Viewed by 8009

Abstract

The 18 kDa translocator protein (TSPO) is highly 0conserved in eukaryotes and prokaryotes. Since its discovery in 1977, numerous studies established the TSPO’s importance for life essential functions. For these studies, synthetic TSPO ligands typically are applied. Tetrapyrroles present endogenous ligands for the TSPO. Tetrapyrroles are also evolutionarily conserved and regulate multiple functions. TSPO and tetrapyrroles regulate each other. In animals TSPO-tetrapyrrole interactions range from effects on embryonic development to metabolism, programmed cell death, response to stress, injury and disease, and even to life span extension. In animals TSPOs are primarily located in mitochondria. In plants TSPOs are also present in plastids, the nuclear fraction, the endoplasmic reticulum, and Golgi stacks. This may contribute to translocation of tetrapyrrole intermediates across organelles’ membranes. As in animals, plant TSPO binds heme and protoporphyrin IX. TSPO-tetrapyrrole interactions in plants appear to relate to development as well as stress conditions, including salt tolerance, abscisic acid-induced stress, reactive oxygen species homeostasis, and finally cell death regulation. In bacteria, TSPO is important for switching from aerobic to anaerobic metabolism, including the regulation of photosynthesis. As in mitochondria, in bacteria TSPO is located in the outer membrane. TSPO-tetrapyrrole interactions may be part of the establishment of the bacterial-eukaryote relationships, i.e., mitochondrial-eukaryote and plastid-plant endosymbiotic relationships. Full article

(This article belongs to the Special Issue Translocator Protein (TSPO))

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Nutritional and Hormonal Regulation of Citrate and Carnitine/Acylcarnitine Transporters: Two Mitochondrial Carriers Involved in Fatty Acid Metabolism

by Anna M. Giudetti, Eleonora Stanca, Luisa Siculella, Gabriele V. Gnoni and Fabrizio Damiano

Int. J. Mol. Sci. 2016, 17(6), 817; https://doi.org/10.3390/ijms17060817 - 25 May 2016

Cited by 31 | Viewed by 12720

Abstract

The transport of solutes across the inner mitochondrial membrane is catalyzed by a family of nuclear-encoded membrane-embedded proteins called mitochondrial carriers (MCs). The citrate carrier (CiC) and the carnitine/acylcarnitine transporter (CACT) are two members of the MCs family involved in fatty acid metabolism. By conveying acetyl-coenzyme A, in the form of citrate, from the mitochondria to the cytosol, CiC contributes to fatty acid and cholesterol synthesis; CACT allows fatty acid oxidation, transporting cytosolic fatty acids, in the form of acylcarnitines, into the mitochondrial matrix. Fatty acid synthesis and oxidation are inversely regulated so that when fatty acid synthesis is activated, the catabolism of fatty acids is turned-off. Malonyl-CoA, produced by acetyl-coenzyme A carboxylase, a key enzyme of cytosolic fatty acid synthesis, represents a regulator of both metabolic pathways. CiC and CACT activity and expression are regulated by different nutritional and hormonal conditions. Defects in the corresponding genes have been directly linked to various human diseases. This review will assess the current understanding of CiC and CACT regulation; underlining their roles in physio-pathological conditions. Emphasis will be placed on the molecular basis of the regulation of CiC and CACT associated with fatty acid metabolism. Full article

(This article belongs to the Special Issue Translocator Protein (TSPO))

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