Translocator Protein (TSPO) in Breast Cancer
Department of Biochemistry and Cancer Biology, Meharry Medical College, 1005 D.B. Todd Blvd., Nashville, TN 37208, USA.Current Molecular Medicine (Impact Factor: 3.62). 02/2012; 12(4):443-57. DOI: 10.2174/1566524011207040443
Several molecular and cellular markers are currently used as prognostic indicators for diagnosis and therapeutic intervention of breast cancer. Although some of these markers have helped clinicians provide an earlier diagnosis (or prognosis), they have failed to provide adequate information about the mechanisms responsible for different stages of tumor malignancy so that more effective anticancer therapies can be developed. Recently translocator protein (TSPO), formerly known as the peripheral benzodiazepine receptor (PBR), has received attention as a potential target for anticancer drug development. It is a well-conserved protein, located at outer-inner mitochondrial membrane contact sites, and is expressed in almost all tissues, although the level of expression varies. TSPO is closely associated with the 32 kDa voltage-dependent anion channel (VDAC) and the 30 kDa adenine nucleotide translocase (ANT), considered to form the core of a mitochondria multiprotein complex [named the mitochondrial permeability transition pore (MPTP)] and plays a role in apoptotic cell death. As the major role of TSPO is steroid biosynthesis, TSPO expression is particularly high in organs involved in steroidogenesis such as the adrenals, testes, ovaries, placenta, prostate, colon, kidney, and cardiovascular system. It is well known that TSPO is over-expressed in highly aggressive tumors, especially those of the breast, and that expression correlates with advancing stages of this malignancy. TSPO expression, nuclear localization, and TSPO-mediated cholesterol transport into the nucleus are involved in breast cancer cell proliferation and aggressive phenotype expression. Hence, it can be used as a biomarker in the stage-dependent diagnosis of this cancer. In addition, cell proliferation, invasion and migration appears to be decreased when treated with high doses of TSPO ligand PK-11195, a compound that may represent a therapeutic agent for the control of breast cancer progression. Control of breast cancer development by consumption of dietary soy protein has been linked to down-regulation of the expression of TSPO-mediated angiogenic signaling molecules. This chapter provides insight into the potential of TSPO as a rational target for the development of novel therapeutics for breast cancer.
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ABSTRACT: Mitochondria are double membrane-enveloped organelles that play a central role in cellular metabolism, calcium homeostasis, redox signaling and cell fates. They function as main generators of ATP, metabolites for the construction of macromolecules and reactive oxygen species. In many cancer cells, mitochondria seem dysfunctional, manifested by a shift of energy metabolism from oxidative phosphorylation to active glycolysis and an increase in reactive oxygen species generation. These metabolic changes are often associated with upregulation of NAD(P)H oxidase. Importantly, the metabolic reprogramming in a cancer cell is mechanistically linked to oncogenic signals. Targeting mitochondria as a cancer therapeutic strategy has attracted much attention in the recent years and multiple review articles in this area have been published. This article attempts to provide an update on recent progress in identification of mitochondria-associated molecules as potential anticancer targets and the respective targeting compounds.Future medicinal chemistry 01/2013; 5(1):53-67. DOI:10.4155/fmc.12.190 · 3.74 Impact Factor
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ABSTRACT: Microarray experiments are capable of determining the relative expression of tens of thousands of genes simultaneously, thus resulting in very large databases. The analysis of these databases and the extraction of biologically relevant knowledge from them are challenging tasks. The identification of potential cancer biomarker genes is one of the most important aims for microarray analysis and, as such, has been widely targeted in the literature. However, identifying a set of these genes consistently across different experiments, researches, microarray platforms, or cancer types is still an elusive endeavor. Besides the inherent difficulty of the large and nonconstant variability in these experiments and the incommensurability between different microarray technologies, there is the issue of the users having to adjust a series of parameters that significantly affect the outcome of the analyses and that do not have a biological or medical meaning. In this study, the identification of potential cancer biomarkers from microarray data is casted as a multiple criteria optimization (MCO) problem. The efficient solutions to this problem, found here through data envelopment analysis (DEA), are associated to genes that are proposed as potential cancer biomarkers. The method does not require any parameter adjustment by the user, and thus fosters repeatability. The approach also allows the analysis of different microarray experiments, microarray platforms, and cancer types simultaneously. The results include the analysis of three publicly available microarray databases related to cervix cancer. This study points to the feasibility of modeling the selection of potential cancer biomarkers from microarray data as an MCO problem and solve it using DEA. Using MCO entails a new optic to the identification of potential cancer biomarkers as it does not require the definition of a threshold value to establish significance for a particular gene and the selection of a normalization procedure to compare different experiments is no longer necessary.Cancer Medicine 04/2013; 2(2):253-65. DOI:10.1002/cam4.69 · 2.50 Impact Factor
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ABSTRACT: Translocator Proteins (18 kDa), TSPOs, are conserved integral membrane proteins. In both eukaryotes and prokaryotes, TSPOs interact with porphyrins, precursors of heme and photosynthetic pigments. Here we demonstrate that bacterial TSPOs catalyze rapid porphyrin degradation in a light- and oxygen-dependent manner. The reaction is in-hibited by a synthetic TSPO ligand PK11195 and by muta-tions of conserved residues, which affect either porphyrin binding or the catalytic activity. We hypothesize that TSPOs are ancient enzymes mediating porphyrin catabolism with the consumption of reactive oxygen species.Biochemistry 05/2013; 52(21). DOI:10.1021/bi400364z · 3.02 Impact Factor
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