Article

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: 3.61). 02/2012; 12(4):443-57. DOI: 10.2174/1566524011207040443
Source: PubMed

ABSTRACT 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.

1 Follower
 · 
109 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: VDAC1 is a multi-functional mitochondrial protein regulating cell life and death•Silencing VDAC1 over-expressed in cancer inhibits cell growth in vivo and in vitro•VDAC1 activities are modulated by associated proteins•A novel mechanism for VDAC1-mediated release of apoptotic proteins is presented•VDAC1-based strategies are proposed for cancer therapeutic applications
    Biochimica et Biophysica Acta (BBA) - Biomembranes 11/2014; DOI:10.1016/j.bbamem.2014.10.040 · 3.43 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Objectives: The Voltage Dependent Anion-Selective Channel (VDAC), the most abundant protein of the outer mitochondrial membrane (OMM), forms the major conduit for metabolite transport across this membrane. It has also been shown to be involved in cell death signalling through interaction with other proteins like Hexokinase and by mediating release of apoptogenic proteins like cyt c from mitochondria. As in case of other channel proteins, functional characterization of purified reconstituted protein by using electrophysiological techniques can be used in development of VDAC targeted drugs. Here we report electrophysiological properties of VDACs (one of the target for cancerous cells) purified from different sources. Methods: Human VDAC1 and rice VDAC4 were heterologously expressed and purified from E. coli BL21 (DE3)-pLysS, while rat and yeast VDACs were purified from mitochondria. Electrophysiological studies of all VDACs were done by using BLM and the data was analysed by using pCLAMP 10 (Axon Instruments). Results: VDACs purified from both the sources showed conserved voltage dependence and channel conductance, however they showed significant difference in dynamics. VDAC purified from mitochondria had relatively short occupancy of each electrophysiological state compared to protein purified from inclusion bodies. Conclusion: Our results suggest that the source of purified protein could be critical for some aspects of channel function.
    International Journal of Pharmacy and Pharmaceutical Sciences 07/2014; 6(7):126-130. · 1.59 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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