The translocator protein (TSPO): A novel target for cancer chemotherapy

Austin, Christopher; Kahlert, Jan; Kassiou, Michael; Rendina, Louis M.

doi:10.1016/j.biocel.2013.03.004

Cited by 90 publications

(72 citation statements)

References 38 publications

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“…In line with the visual interpretation, the percentage overlap with VOIs representing tumor progression is higher for 123 I-CLINDE than for 18 F-FET (21% vs. 8% and 72% vs. 55%) in patients 1 and 3. The findings correspond to previous reports demonstrating the contribution of TSPO to the uncontrolled cellular proliferation of glioma cells (22) and the correlation between TSPO density in surgically removed glioma tissue with clinical parameters such as survival time and tumor cell proliferation index (8,9). TSPO is expressed in glioma cells, suggesting that this method may be a more sensitive and specific marker of ongoing tumor cell proliferation and progression than conventional imaging methods.…”

Section: Discussionsupporting

confidence: 91%

TSPO Imaging in Glioblastoma Multiforme: A Direct Comparison Between ¹²³I-CLINDE SPECT, ¹⁸F-FET PET, and Gadolinium-Enhanced MR Imaging

et al. 2015

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Section: Discussionsupporting

confidence: 91%

TSPO Imaging in Glioblastoma Multiforme: A Direct Comparison Between ¹²³I-CLINDE SPECT, ¹⁸F-FET PET, and Gadolinium-Enhanced MR Imaging

et al. 2015

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“…Pathological overexpression of TSPO has been reported in several cancers like colon, breast, and skin cancers (31,32). A strong correlation between the aggressive cancer phenotype and expression levels of TSPO has been established in several studies (33)(34)(35).…”

Section: Mammalian Translocator Protein (Tspo)mentioning

confidence: 99%

Mitochondrial Translocator Protein (TSPO) Function Is Not Essential for Heme Biosynthesis

Zhao

Mukai

et al. 2016

Journal of Biological Chemistry

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Function of the mammalian translocator protein (TSPO; previously known as the peripheral benzodiazepine receptor) remains unclear because its presumed role in steroidogenesis and mitochondrial permeability transition established using pharmacological methods has been refuted in recent genetic studies. Protoporphyrin IX (PPIX) is considered a conserved endogenous ligand for TSPO. In bacteria, TSPO was identified to regulate tetrapyrrole metabolism and chemical catalysis of PPIX in the presence of light, and in vertebrates, TSPO function has been linked to porphyrin transport and heme biosynthesis. Positive correlation between high TSPO expression in cancer cells and susceptibility to photodynamic therapy based on their increased ability to convert the precursor 5-aminolevulinic acid (ALA) to PPIX appeared to reinforce this mechanism. In this study, we used TSPO knock-out (Tspo ؊/؊ ) mice, primary cells, and different tumor cell lines to examine the role of TSPO in erythropoiesis, heme levels, PPIX biosynthesis, phototoxic cell death, and mitochondrial bioenergetic homeostasis. In contrast to expectations, our results demonstrate that TSPO deficiency does not adversely affect erythropoiesis, heme biosynthesis, bioconversion of ALA to PPIX, and porphyrin-mediated phototoxic cell death. TSPO expression levels in cancer cells do not correlate with their ability to convert ALA to PPIX. In fibroblasts, we observed that TSPO deficiency decreased the oxygen consumption rate and mitochondrial membrane potential (⌬⌿m) indicative of a cellular metabolic shift, without a negative impact on porphyrin biosynthetic capability. Based on these findings, we conclude that mammalian TSPO does not have a critical physiological function related to PPIX and heme biosynthesis.Mammalian translocator protein (TSPO), 2 previously known as the peripheral benzodiazepine receptor (1), is a highly conserved protein enriched in the outer mitochondrial membrane (2). Despite extensive efforts to characterize TSPO, its precise physiological function remains elusive (3, 4). High levels of TSPO expression in steroidogenic cells, its localization to the outer mitochondrial membrane, and increased steroid production upon pharmacological binding led to the primary prospective model that TSPO was a mitochondrial cholesterol transporter essential for steroidogenesis (5). In recent studies using precise genetic tools, we and others have systematically refuted the involvement of TSPO in this process (6 -10). Similarly, copurification of TSPO with putative members of the mitochondrial permeability transition pore (MPTP) (11) and effects mediated by TSPO binding drugs on modulating apoptosis (12, 13) resulted in a secondary model that TSPO was associated with MPTP function and cell death (14). Again, recent discovery of the molecular identity of MPTP (15) Binding of porphyrins to TSPO has been a consistent property reported in bacteria (18), plants (19), and animals (17). In Rhodobacter sphaeroides, TSPO was found localized to the outer membrane (18) and pl...

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“…In view of this evidence, experimental studies proposed the TSPO as a target for selective delivery of anticancer drugs into glioma cells or to be exploited as a transporter of drugcontaining nanoparticles (7)(8)(9). TSPO upregulation in cancer cells and its function in their growth, survival, and migration have recently attracted considerable attention (10).…”

mentioning

confidence: 99%

The 18-kDa Mitochondrial Translocator Protein in Human Gliomas: An ¹¹C-(R)PK11195 PET Imaging and Neuropathology Study

Su¹,

Roncaroli²,

Durrenberger³

et al. 2015

J Nucl Med

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The 18-kDa mitochondrial translocator protein (TSPO) is upregulated in high-grade astrocytomas and can be imaged by PET using the selective radiotracer 11 C-(R)PK11195. We investigated 11 C-(R)PK11195 binding in human gliomas and its relationship with TSPO expression in tumor tissue and glioma-associated microglia/macrophages (GAMs) within the tumors. Methods: Twenty-two glioma patients underwent dynamic 11 C-(R)PK11195 PET scans and perfusion MR imaging acquisition. Parametric maps of 11 C-(R)PK11195 binding potential (BP ND ) were generated. Coregistered MR/PET images were used to guide tumor biopsy. The tumor tissue was quantitatively assessed for TSPO expression and infiltration of GAMs using immunohistochemistry and double immunofluorescence. The imaging and histopathologic parameters were compared among different histotypes and grades and correlated with each other. Results: BP ND of 11 C-(R)PK11195 in high-grade gliomas was significantly higher than in low-grade astrocytomas and low-grade oligodendrogliomas. TSPO in gliomas was expressed predominantly by neoplastic cells, and its expression correlated positively with BP ND in the tumors. GAMs only partially contributed to the overall TSPO expression within the tumors, and TSPO expression in GAMs did not correlate with tumor BP ND . Conclusion: PET with 11 C-(R)PK11195 in human gliomas predominantly reflects TSPO expression in tumor cells. It therefore has the potential to effectively stratify patients who are suitable for TSPO-targeted treatment.

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The translocator protein (TSPO): A novel target for cancer chemotherapy

Cited by 90 publications

References 38 publications

TSPO Imaging in Glioblastoma Multiforme: A Direct Comparison Between ¹²³I-CLINDE SPECT, ¹⁸F-FET PET, and Gadolinium-Enhanced MR Imaging

TSPO Imaging in Glioblastoma Multiforme: A Direct Comparison Between ¹²³I-CLINDE SPECT, ¹⁸F-FET PET, and Gadolinium-Enhanced MR Imaging

Mitochondrial Translocator Protein (TSPO) Function Is Not Essential for Heme Biosynthesis

The 18-kDa Mitochondrial Translocator Protein in Human Gliomas: An ¹¹C-(R)PK11195 PET Imaging and Neuropathology Study

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The translocator protein (TSPO): A novel target for cancer chemotherapy

Cited by 90 publications

References 38 publications

TSPO Imaging in Glioblastoma Multiforme: A Direct Comparison Between 123I-CLINDE SPECT, 18F-FET PET, and Gadolinium-Enhanced MR Imaging

TSPO Imaging in Glioblastoma Multiforme: A Direct Comparison Between 123I-CLINDE SPECT, 18F-FET PET, and Gadolinium-Enhanced MR Imaging

Mitochondrial Translocator Protein (TSPO) Function Is Not Essential for Heme Biosynthesis

The 18-kDa Mitochondrial Translocator Protein in Human Gliomas: An 11C-(R)PK11195 PET Imaging and Neuropathology Study

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TSPO Imaging in Glioblastoma Multiforme: A Direct Comparison Between ¹²³I-CLINDE SPECT, ¹⁸F-FET PET, and Gadolinium-Enhanced MR Imaging

TSPO Imaging in Glioblastoma Multiforme: A Direct Comparison Between ¹²³I-CLINDE SPECT, ¹⁸F-FET PET, and Gadolinium-Enhanced MR Imaging

The 18-kDa Mitochondrial Translocator Protein in Human Gliomas: An ¹¹C-(R)PK11195 PET Imaging and Neuropathology Study