Androgens and androgen receptor (AR) play a critical role not only in normal prostate development, but also in prostate cancer. For that reason, androgen deprivation therapy (ADT) is the primary treatment for prostate cancer. However, the majority of patients develop castration-resistant prostate cancer, which eventually leads to mortality. Novel therapeutic approaches, including dietary changes, have been explored. Soy isoflavones have become a focus of interest because of their positive health benefits on numerous diseases, particularly hormone-related cancers, including prostate and breast cancers. An important strategy for the prevention and/or treatment of prostate cancer might thus be the action of soy isoflavones on the AR signaling pathway. The current review article provides a detailed overview of the anticancer potential of soy isoflavones (genistein, daidzein and glycitein), as mediated by their effect on AR. Contents 1. Introduction 2. AR: Structure, function and mechanism of action 3. Isoflavones: Structures, sources and general biological activities 4. Hormone-like properties of isoflavones 5. Isoflavones as AR modulators: Interactions with AR 6. Isoflavones as AR modulators: In vitro and in vivo studies and clinical trials on prostate cancer 7. Isoflavones and metabolism of steroid hormones 8. Conclusions
Overload or dysfunction of ubiquitin-proteasome system (UPS) is implicated in mechanisms of neurodegeneration associated with neurodegenerative diseases, e.g. Parkinson and Alzheimer disease, and ischemia-reperfusion injury. The aim of this study was to investigate the possible association between viability of neuroblastoma SH-SY5Y and glioblastoma T98G cells treated with bortezomib, inhibitor of 26S proteasome, and accumulation of ubiquitin-conjugated proteins with respect to direct cytotoxicity of aggregates of ubiquitin-conjugated proteins. Bortezomib-induced death of SH-SY5Y cells was documented after 24 h of treatment while death of T98G cells was delayed up to 48 h. Already after 4 h of treatment of both SH-SY5Y and T98G cells with bortezomib, increased levels of both ubiquitin-conjugated proteins with molecular mass more than 150 kDa and Hsp70 were observed whereas Hsp90 was elevated in T98G cells and decreased in SH-SY5Y cells. With respect to the cell death mechanism, we have documented bortezomib-induced activation of caspase 3 in SH-SY5Y cells that was probably a result of increased expression of pro-apoptotic proteins, PUMA and Noxa. In T98G cells, bortezomib-induced expression of caspase 4, documented after 24 h of treatment, with further activation of caspase 3, observed after 48 h of treatment. The delay in activation of caspase 3 correlated well with the delay of death of T98G cells. Our results do not support the possibility about direct cytotoxicity of aggregates of ubiquitin-conjugated proteins. They are more consistent with a view that proteasome inhibition is associated with both transcription-dependent and -independent changes in expression of pro-apoptotic proteins and consequent cell death initiation associated with caspase 3 activation.
Abstract. Androgens play an important role during the development of both normal prostate epithelium and prostate cancer and variants of genes involved in androgen metabolism may be related to an increased risk of prostate disease. Cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17A1) is a key regulatory enzyme in the steroidogenic pathway; it catalyses both 17α-hydroxylase and 17,20-lyase activities and is essential for the production of both androgens and glucocorticoids. In this review, we focus on the structure and enzymatic activity of CYP17A1 and the mechanism of modulation of CYP17A1 activities. We discuss the relationship between common genetic variations in CYP17A1 gene and prostate cancer risk and the main effects of these variations on the prediction of susceptibility and clinical outcomes of prostate cancer patients. The mechanism of action, the efficacy and the clinical potential of CYP17A1 inhibitors in prostate cancer are also summarized.
Normobaric hyperoxia is applied for the treatment of a wide variety of diseases and clinical conditions related to ischemia or hypoxia, but it can increase the risk of tissue damage and its efficiency is controversial. In the present study, we analyzed cardiac mitochondrial proteome derived from guinea pigs after 60 h exposure to 100% molecular oxygen (NBO) or O enriched with oxygen cation (NBO+). Two-dimensional gel electrophoresis followed by MALDI-TOF/TOF mass spectrometry identified twenty-two different proteins (among them ten nonmitochondrial) that were overexpressed in NBO and/or NBO+ group. Identified proteins were mainly involved in cellular energy metabolism (tricarboxylic acid cycle, oxidative phosphorylation, glycolysis), cardioprotection against stress, control of mitochondrial function, muscle contraction, and oxygen transport. These findings support the viewpoint that hyperoxia is associated with cellular stress and suggest complex adaptive responses which probably contribute to maintain or improve intracellular ATP levels and contractile function of cardiomyocytes. In addition, the results suggest that hyperoxia-induced cellular stress may be partially attenuated by utilization of NBO+ treatment.
Oncoproteomic technologies offer a complementary approach to the understanding of cancer proteins' function and the translation of molecular knowledge into clinical practice. Our aim was to compare the proteomic profiles of prostate tumors versus benign prostatic hyperplasia (BPH) tissues in order to identify modulated proteins as the potential biomarkers for prostate cancer. Proteins extracted from twenty prostate cancer tissue specimens and ten BPH tissues were analyzed by two-dimensional electrophoresis (2-DE) coupled with MALDI-TOF mass spectrometry. Western blot and quantitative real-time PCR (RT-PCR) were performed to confirm the different amount of protein biomarkers revealed by 2DE combined with MALDI mass spectrometry. We found 42 spots whose expression in the prostate was altered more than 1.5-fold compared with BPH tissue (p < 0.05). These spots represented ten different proteins that were identified by a database search after mass spectrometry: they comprised proteins involved in the regulation of actin dynamics, the cytoskeleton, and cell motility (ACTG2, ACTA2, TPM1, DES, VIM, FLNA, and TAGLN), heat shock protein-27 (Hsp27), and proteins with other functions (TR and RANBP3). Subsequent western blot and RT-PCR assays for DES, VIM, TAGLN, and Hsp27 in prostate tumor tissues and BPH tissues confirmed the observations obtained by proteomic analysis. The cytoskeletal and cytoskeleton-associated proteins identified by this approach might be useful molecular targets for prostate cancer diagnostics and may contribute to novel therapies for prostate cancer.
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