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: 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.
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