MYC Cooperates with AKT in Prostate Tumorigenesis and Alters Sensitivity to mTOR Inhibitors

MYC and phosphoinositide 3-kinase (PI3K)-pathway deregulation are common in human prostate cancer. Through examination of 194 human prostate tumors, we observed statistically significant co-occurrence of MYC amplification and PI3K-pathway alteration, raising the possibility that these two lesions cooperate in prostate cancer progression. To investigate this, we generated bigenic mice in which both activated human AKT1 and human MYC are expressed in the prostate (MPAKT/Hi-MYC model). In contrast to mice expressing AKT1 alone (MPAKT model) or MYC alone (Hi-MYC model), the bigenic phenotype demonstrates accelerated progression of mouse prostate intraepithelial neoplasia (mPIN) to microinvasive disease with disruption of basement membrane, significant stromal remodeling and infiltration of macrophages, B- and T-lymphocytes, similar to inflammation observed in human prostate tumors. In contrast to the reversibility of mPIN lesions in young MPAKT mice after treatment with mTOR inhibitors, Hi-MYC and bigenic MPAKT/Hi-MYC mice were resistant. Additionally, older MPAKT mice showed reduced sensitivity to mTOR inhibition, suggesting that additional genetic events may dampen mTOR dependence. Since increased MYC expression is an early feature of many human prostate cancers, these data have implications for treatment of human prostate cancers with PI3K-pathway alterations using mTOR inhibitors

Dominant negative knockout of p53 abolishes ErbB2-dependent apoptosis and permits growth acceleration in human breast cancer cells

We previously reported that the ErbB2 oncoprotein prolongs and amplifies growth factor signalling by impairing ligand-dependent downregulation of hetero-oligomerised epidermal growth factor receptors. Here we show that treatment of A431 cells with different epidermal growth factor receptor ligands can cause growth inhibition to an extent paralleling ErbB2 tyrosine phosphorylation. To determine whether such growth inhibition signifies an interaction between the cell cycle machinery and ErbB2-dependent alterations of cell signalling kinetics, we used MCF7 breast cancer cells (which express wild-type p53) to create transient and stable ErbB2 transfectants (MCF7-B2). Compared with parental cells, MCF7-B2 cells are characterised by upregulation of p53, p21WAF and Myc, downregulation of Bcl2, and apoptosis. In contrast, MCF7-B2 cells co-transfected with dominant negative p53 (MCF7-B2/Δp53) exhibit reduced apoptosis and enhanced growth relative to both parental MCF7-B2 and control cells. These data imply that wild-type p53 limits survival of ErbB2-overexpressing breast cancer cells, and suggest that signals of varying length and/or intensity may evoke different cell outcomes depending upon the integrity of cell cycle control genes. We submit that acquisition of cell cycle control defects may play a permissive role in ErbB2 upregulation, and that the ErbB2 overexpression phenotype may in turn select for the survival of cells with p53 mutations or other tumour suppressor gene defects

Synthesis, Biological Evaluation and Mechanism Studies of Deoxytylophorinine and Its Derivatives as Potential Anticancer Agents

Previous studies indicated that (+)-13a-(S)-Deoxytylophorinine (1) showed profound anti-cancer activities both in vitro and in vivo and could penetrate the blood brain barrier to distribute well in brain tissues. CNS toxicity, one of the main factors to hinder the development of phenanthroindolizidines, was not obviously found in 1. Based on its fascinating activities, thirty-four derivatives were designed, synthesized; their cytotoxic activities in vitro were tested to discover more excellent anticancer agents. Considering the distinctive mechanism of 1 and interesting SAR of deoxytylophorinine and its derivatives, the specific impacts of these compounds on cellular progress as cell signaling transduction pathways and cell cycle were proceeded with seven representative compounds. 1 as well as three most potent compounds, 9, 32, 33, and three less active compounds, 12, 16, 35, were selected to proform this study to have a relatively deep view of cancer cell growth-inhibitory characteristics. It was found that the expressions of phospho-Akt, Akt, phospho-ERK, and ERK in A549 cells were greater down-regulated by the potent compounds than by the less active compounds in the Western blot analysis. To the best of our knowledge, this is the first report describing phenanthroindolizidines alkaloids display influence on the crucial cell signaling proteins, ERK. Moreover, the expressions of cyclin A, cyclin D1 and CDK2 proteins depressed more dramatically when the cells were treated with 1, 9, 32, and 33. Then, these four excellent compounds were subjected to flow cytometric analysis, and an increase in S-phase was observed in A549 cells. Since the molecular level assay results of Western blot for phospho-Akt, Akt, phospho-ERK, ERK, and cyclins were relevant to the potency of compounds in cellular level, we speculated that this series of compounds exhibit anticancer activities through blocking PI3K and MAPK signaling transduction pathways and interfering with the cell cycle progression

Models of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a major global health problem and is predicted to become the third most common cause of death by 2020. Apart from the important preventive steps of smoking cessation, there are no other specific treatments for COPD that are as effective in reversing the condition, and therefore there is a need to understand the pathophysiological mechanisms that could lead to new therapeutic strategies. The development of experimental models will help to dissect these mechanisms at the cellular and molecular level. COPD is a disease characterized by progressive airflow obstruction of the peripheral airways, associated with lung inflammation, emphysema and mucus hypersecretion. Different approaches to mimic COPD have been developed but are limited in comparison to models of allergic asthma. COPD models usually do not mimic the major features of human COPD and are commonly based on the induction of COPD-like lesions in the lungs and airways using noxious inhalants such as tobacco smoke, nitrogen dioxide, or sulfur dioxide. Depending on the duration and intensity of exposure, these noxious stimuli induce signs of chronic inflammation and airway remodelling. Emphysema can be achieved by combining such exposure with instillation of tissue-degrading enzymes. Other approaches are based on genetically-targeted mice which develop COPD-like lesions with emphysema, and such mice provide deep insights into pathophysiological mechanisms. Future approaches should aim to mimic irreversible airflow obstruction, associated with cough and sputum production, with the possibility of inducing exacerbations

GRB 120422A/SN 2012bz: Bridging the gap between low- and high-luminosity gamma-ray bursts

Context. At low redshift, a handful of gamma-ray bursts (GRBs) have been discovered with luminosities that are substantially lower (Liso ≲ 1048.5 erg s-1) than the average of more distant ones (Liso ≳ 1049.5 erg s-1). It has been suggested that the properties of several low-luminosity (low-L) GRBs are due to shock break-out, as opposed to the emission from ultrarelativistic jets. This has led to much debate about how the populations are connected. Aims. The burst at redshift z = 0.283 from 2012 April 22 is one of the very few examples of intermediate-L GRBs with a γ-ray luminosity of Liso ~ 1049.6−49.9 erg s-1 that have been detected up to now. With the robust detection of its accompanying supernova SN 2012bz, it has the potential to answer important questions on the origin of low- and high-L GRBs and the GRB-SN connection. Methods. We carried out a spectroscopy campaign using medium- and low-resolution spectrographs with 6–10-m class telescopes, which covered a time span of 37.3 days, and a multi-wavelength imaging campaign, which ranged from radio to X-ray energies over a duration of ~270 days. Furthermore, we used a tuneable filter that is centred at Hα to map star-formation in the host and the surrounding galaxies. We used these data to extract and model the properties of different radiation components and fitted the spectral energy distribution to extract the properties of the host galaxy. Results. Modelling the light curve and spectral energy distribution from the radio to the X-rays revealed that the blast wave expanded with an initial Lorentz factor of Γ0 ~ 50, which is a low value in comparison to high-L GRBs, and that the afterglow had an exceptionally low peak luminosity density of ≲2 × 1030 erg s-1 Hz-1 in the sub-mm. Because of the weak afterglow component, we were able to recover the signature of a shock break-out in an event that was not a genuine low-L GRB for the first time. At 1.4 hr after the burst, the stellar envelope had a blackbody temperature of kBT ~ 16 eV and a radius of ~7 × 1013 cm (both in the observer frame). The accompanying SN 2012bz reached a peak luminosity of MV = −19.7 mag, which is 0.3 mag more luminous than SN 1998bw. The synthesised nickel mass of 0.58 M⊙, ejecta mass of 5.87 M⊙, and kinetic energy of 4.10 × 1052 erg were among the highest for GRB-SNe, which makes it the most luminous spectroscopically confirmed SN to date. Nebular emission lines at the GRB location were visible, which extend from the galaxy nucleus to the explosion site. The host and the explosion site had close-to-solar metallicity. The burst occurred in an isolated star-forming region with an SFR that is 1/10 of that in the galaxy’s nucleus. Conclusions. While the prompt γ-ray emission points to a high-L GRB, the weak afterglow and the low Γ0 were very atypical for such a burst. Moreover, the detection of the shock break-out signature is a new quality for high-L GRBs. So far, shock break-outs were exclusively detected for low-L GRBs, while GRB 120422A had an intermediate Liso of ~1049.6−49.9 erg s-1. Therefore, we conclude that GRB 120422A was a transition object between low- and high-L GRBs, which supports the failed-jet model that connects low-L GRBs that are driven by shock break-outs and high-L GRBs that are powered by ultra-relativistic jets

Bio-sociodiversidade: preservação e mercado

VÁRIOS estudos vêm revelando possibilidades de aproveitamento de conhecimentos indígenas e de outras culturas tradicionais, entre eles, medicamentos, cosméticos, novos materiais, alimentos, sementes e conservantes como produtos de mercado. A prática do mercado vem sendo a de apropriar-se desses bens culturais, registrá-los após adaptações e devolvê-los como mercadorias protegidas por patentes, inclusive aos países onde tais conhecimentos foram desenvolvidos, geralmente ao sul do Equador. Frente à escala da degradação social e ambiental, como na Amazônia, surgiu um novo otimismo, o de que resultados financeiros de tais produtos pudessem reverter às populações, modificando-se a legislação internacional e associando-se cooperativas de produtores com a biotecnologia e as transnacionais. O mercado, o principal adversário da preservação da bio e da sociodiversidade, seria assim convidado - empresas e consumidores - a tornar-se aliado da manutenção da floresta em pé e da diferença cultural, por exemplo, mediante certificados de origem. No entanto, são numerosos os entraves para que essas populações possam abrir brechas no mercado, ou nos sistemas internacionais de registro de patentes, frente à lógica da concentração de capital e tecnologia.<br>SEVERAL studies have been revealing prospects of capitalizing on native knowledge and traditional cultures in order to launch new market products, such as drugs, cosmetics, new materials, foods, seeds and preservers. The market has adopted the practice of appropriating such cultural goods, which after slight adaptation are registered and turned out as patent-protected products and sold even to the countries where that knowledge was first developed, south of the equator as a rule. Vis-à-vis the social and evironmental degradation scale, as is the case of the Amazon area, a new optimism has risen: the hope that financial results from such products could benefit the native peoples, through the alteration of international legislation and the association of producers cooperatives with transnational companies. The market, the main opponent of bio- and sociodiversity, would thus be invited - both producers and consumers - to support the maintenance of the standing forest and cultural difference, for example, by means of origin certificates. Nevertheless, many are the obstacles preventing the native peoples from making a breakthrough either in the market or in the patent registration international systems vis-à-vis the capital and technology concentration logic

Hypothermic stress leads to activation of Ras-Erk signaling

The small GTPase Ras is converted to the active, GTP-bound state during exposure of vertebrate cells to hypothermic stress. This activation occurs more rapidly than can be accounted for by spontaneous nucleotide exchange. Ras–guanyl nucleotide exchange factors and Ras GTPase–activating proteins have significant activity at 0°C in vitro, leading to the hypothesis that normal Ras regulators influence the relative amounts of Ras-GTP and Ras-GDP at low temperatures in vivo. When hypothermic cells are warmed to 37°C, the Raf-Mek-Erk protein kinase cascade is activated. After prolonged hypothermic stress, followed by warming to physiologic temperature, cultured fibroblasts assume a rounded morphology, detach from the substratum, and die. All of these biologic responses are attenuated by pharmacologic inhibition of Mek. Previously, it had been found that low temperature blocks acute growth factor signaling to Erk. In the present study, we found that this block occurs at the level of Raf activation. Temperature regulation of Ras signaling could help animal cells respond appropriately to hypothermic stress, and Ras-Erk signaling can be manipulated to improve the survival of cells in cold storage

Two distinct phosphoinositide 3-kinases mediate polypeptide growth factor-stimulated PKB activation

Eight human isoforms of phosphoinositide 3-kinases (PI3Ks) exist, but their individual functions remain poorly understood. Here, we show that different human small cell lung carcinoma (SCLC) cell lines overexpress distinct subsets of class I(A) and II PI3Ks, which results in striking differences in the signalling cascades activated by stem cell factor (SCF). Over expression of class I(A) p85/p110α in SCLC cells increased SCF-stimulated protein kinase B (PKB) activation and cell growth, but did not affect extracellular signal-regulated kinase (Erk) or glycogen synthase kinase-3 (GSK-3). This effect was selective, since it was not observed in SCLC cell lines overexpressing p85/p110β or p85/p110δ. The SCF receptor associated with both class I(A) p85 and class II PI3KC2β, and both enzymes contributed to SCF-stimulated PKB activity. A dominant-negative PI3KC2β blocked both PKB activation and SCLC cell growth in response to SCF. Together our data provide novel insights into the specificity and functional significance of PI3K signalling in human cancer