The Major Heat Shock Proteins, Hsp70 and Hsp90, in 2-Methoxyestradiol-Mediated Osteosarcoma Cell Death Model

2-Methoxyestradiol is one of the natural 17β-estradiol derivatives and a potential novel anticancer agent currently being under evaluation in advanced phases of clinical trials. However, the mechanism of anticancer action of 2-methoxyestradiol has not been yet fully established. In our previous studies we have demonstrated that 2-methoxyestradiol selectively induces the expression and nuclear translocation of neuronal nitric oxide synthase in osteosarcoma 143B cells. Heat shock proteins (Hsps) are factors involved in the regulation of expression and activity of nitric oxide synthases. Herein, we chose osteosarcoma cell lines differed in metastatic potential, metastatic 143B and highly metastatic MG63.2 cells, in order to further investigate the anticancer mechanism of 2-methoxyestradiol. The current study aimed to determine the role of major heat shock proteins, Hsp90 and Hsp70 in 2-methoxyestradiol-induced osteosarcoma cell death. We focused on the implication of Hsp90 and Hsp70 in control under expression of neuronal nitric oxide synthase, localization of the enzyme, and further generation of nitro-oxidative stress. To give the insight into the role of Hsp90 in regulation of anticancer efficacy of 2-methoxyestradiol, we used geldanamycin as a potent Hsp90 inhibitor. Herein, we evidenced that inhibition of Hsp90 controls the protein expression of 2-methoxyestradiol-induced neuronal nitric oxide synthase and inhibits enzyme nuclear translocation. We propose that decreased level of neuronal nitric oxide synthase protein after a combined treatment with 2-methoxyestradiol and geldanamycin is directly associated with the accompanying upregulation of Hsp70 and downregulation of Hsp90. This interaction resulted in abrogation of anticancer efficacy of 2-methoxyestradiol by geldanamycin

Again on coherent states in magnetic-solenoid field

This article completes our study of coherent states in the so-called magnetic-solenoid field (a colinear combination of a constant uniform magnetic field and Aharonov-Bohm solenoid field) presented in JPA 2010 and 2011. Here we succeeded to prove nontrivial completeness relations for non-relativistic and relativistic coherent states in such a field. In addition, we solve here the relevant Stieltjes moment problem and present a comparative analysis of our coherent states and the well-known in the case of pure uniform magnetic field Malkin-Man'ko coherent states.Comment: 9 page

Association between serum heat shock proteins and gamma-delta t cells—an outdated clue or a new direction in searching for an anticancer strategy? A short report

HSPs demonstrate a strong association with gamma-delta (γδ) T cells. Most of the studies regarding interactions between the parameters were conducted in the 1990s. Despite promising results, the concept of targeting γδ T cells by HSPs seems to be a forgotten direction due to potent non-peptidic phosphoantigens rather than HSPs have been found to be the essential stimulatory components for human γδ cells. Currently, with greater knowledge of lymphocyte diversity, and more accurate diagnostic methods, we decided to study the correlation once again in the neoplas-tic condition. Twenty-one children with newly diagnosed acute lymphoblastic leukaemia (ALL) were enrolled on the study. Serum HSP90 concentrations were evaluated by an enzyme-linked immunosorbent assay (ELISA), subsets of γδ T cells (CD3+ γδ, CD3+ γδ HLA/DR+, CD4+ γδ and CD8+ γδ) by flow cytometry. We have shown statistically relevant correlations between serum HSP90 and CD3+ HLA/DR+ γδ T cells in paediatric ALL at diagnosis (R = 0.53, p < 0.05), but not after induction chemotherapy. We also have demonstrated decreased levels of both serum HSP90 and CD3+ HLA/DR+ γδ T cells before treatment, which may indirectly indicate dose-dependent unknown interaction between the parameters. The results of our study may be a good introduction to research on the association between HSPs and CD3+ HLA/DR+ γδ T cells, which could be an interesting direction for the development of anti-cancer strategies, not just for childhood ALL

Unc119, a Novel Activator of Lck/Fyn, Is Essential for T Cell Activation

The first step in T cell receptor for antigen (TCR) signaling is the activation of the receptor-bound Src kinases, Lck and Fyn. The exact mechanism of this process is unknown. Here, we report that the novel Src homology (SH) 3/SH2 ligand–Uncoordinated 119 (Unc119) associates with CD3 and CD4, and activates Lck and Fyn. Unc119 overexpression increases Lck/Fyn activity in T cells. In Unc119-deficient T cells, Lck/Fyn activity is dramatically reduced with concomitant decrease in interleukin 2 production and cellular proliferation. Reconstitution of cells with Unc119 reverses the signaling and functional outcome. Thus, Unc119 is a receptor-associated activator of Src-type kinases. It provides a novel mechanism of signal generation in the TCR complex

DNA strand breaks induced by nuclear hijacking of neuronal NOS as an anti-cancer effect of 2-methoxyestradiol

2-Methoxyestradiol (2-ME) is a physiological metabolite of 17β-estradiol. At pharmacological concentrations, 2-ME inhibits colon, breast and lung cancer in tumor models. Here we investigated the effect of physiologically relevant concentrations of 2-ME in osteosarcoma cell model. We demonstrated that 2-ME increased nuclear localization of neuronal nitric oxide synthase, resulting in nitro-oxidative DNA damage. This in turn caused cell cycle arrest and apoptosis in osteosarcoma cells. We suggest that 2-ME is a naturally occurring hormone with potential anti-cancer properties

RSK1 promotes murine breast cancer growth and metastasis

Introduction. Triple-negative breast cancer (TNBC), representing over 15% of all breast cancers, has a poorerprognosis than other subtypes. There is no effective targeted treatment available for the TNBC sufferers. Ribosomal S6 kinases (RSKs) have been previously proposed as drug targets for TNBC based on observations that 85% of these tumors express activated RSKs.Materials and methods. Herein we examined an involvement of RSK1 (p90 ribosomal S6 kinase 1) in a regulation of TNBC growth and metastatic spread in an animal model, which closely imitates human disease. Micewere inoculated into mammary fat pad with 4T1 cells or their RSK1-depleted variant. We examined tumorgrowth and formation of pulmonary metastasis. Boyden chamber, wound healing and soft agarose assays wereperformed to evaluate cells invasion, migration and anchorage-independent growth.Results. We found that RSK1 promoted tumor growth and metastasis in vivo. After 35 days all animals inoculatedwith control cells developed tumors while in the group injected with RSK1-negative cells, there were 75%tumor-bearing mice. Average tumor mass was estimated as 1.16 g and 0.37 g for RSK1-positive vs. -negativesamples, respectively (p < 0.0001). Quantification of the macroscopic pulmonary metastases indicated that micewith RSK1-negative tumors developed approximately 85% less metastatic foci on the lung surface (p < 0.001).This has been supported by in vitro data presenting that RSK1 promoted anchorage-independent cell growthand migration. Moreover, RSK1 knock-down corresponded with decreased expression of cell cycle regulatingproteins, i.e. cyclin D3, CDK6 and CDK4.Conclusions. We provide evidence that RSK1 supports tumor growth and metastatic spread in vivo as well asin vitro migration and survival in non-adherent conditions. Further studies of RSK1 involvement in TNBC progression may substantiate our findings, laying the foundations for development of anti-RSK1-based therapeuticstrategies in the management of patients with TNBC

Plausible role of estrogens in pathogenesis, progression and therapy of lung cancer

Malignant neoplasms are among the most common diseases and are responsible for the majority of deaths in the developed world. In contrast to men, available data show a clear upward trend in the incidence of lung cancer in women, making it almost as prevalent as breast cancer. Women might be more susceptible to the carcinogenic effect of tobacco smoke than men. Furthermore, available data indicate a much more frequent mutation of the tumor suppressor genep53 in non-small cell lung cancer (NSCLC) female patients compared to males. Another important factor, however, might lie in the female sex hormones, whose mitogenic or carcinogenic effect is well known. Epidemiologic data show a correlation between hormone replacement therapy (HRT) or oral contraceptives (OCs), and increased mortality rates due to the increased incidence of malignant tumors, including lung cancer. Interestingly, two types of estrogen receptors have been detected in lung cancer cells: ERα and ERβ. The presence of ERα has been detected in tissues and non-small-cell lung carcinoma (NSCLC) cell lines. In contrast, overexpression of ERβ is a prognostic marker in NSCLC. Herein, we summarize the current knowledge on the role of estrogens in the etiopathogenesis of lung cancer, as well as biological, hormonal and genetic sex-related differences in this neoplasm

On the β-detection efficiency of a combined Si and plastic stack detector for DESPEC

A Geant4 simulation has been carried out in order to determine the B-detection efficiency of a rare isotope beam implantation setup, for decay spectroscopy experiments, comprising a number of Double Sided Silicon Strip Detectors (DSSSDs) and two plastic scintillation detectors placed upstream and downstream. The absolute efficiency for the emitted B-particle detection from radioactive fragments implanted in the DSSSDs using fast-timing plastic-scintillator detector, is calculated. The detection efficiency of the setup has been studied with two different distances between the Si layers and plastics. The requirement for the thickness of the Si detector layers and its implication on the B-detection effciency has been investigated for 1 mm and 300 um thickness of Si layers. The combined efficiency of DSSSD and plastic detectors were also simulated for two different thicknesses of the DSSSD