Doxazosin induces apoptosis in PTEN–positive androgen-independent PC cells via inhibition of Akt activation

Doxazosin, a selective α1-adrenoreceptor antagonist widely used in the management of benign prostatic hyperplasia (BPH), has been shown to induce apoptosis in androgen-independent (AI) and PTEN (phosphatases and tensin homolog)-negative prostate cancer (PC) cells. The objective of this study was to assess the effects of doxazosin on the growth of PC cells with a functional PTEN/PI3K/Akt pathway in relation to cell androgen sensitivity and Bcl-2 expression. Material and methods. The DU145 cell line and two derivatives: 1) DKC9 [DU145 (Bcl2 +/+)] and 2) DAR19 [DU145 (AR+/+)] were used. The effect of doxazosin on i) cell proliferation and ii) Akt phosphorylation was measured using the MTT assay and Western blotting, respectively. Results. Doxazosin caused significant concentration, but not time-dependent, decrease in cell viability. The threshold of sensitivity to the compound differed between the cell lines and was the lowest in the parental cell line. In DAR 19 cells, AR-mediated signaling further increased cell resistance to doxazosin. In all cell lines, doxazosin-induced apoptosis was rescued by EGF stimulation and, in DAR19 cells, by AR activation. Doxazosin reduced basal and EGF-/DHT-induced Akt phosphorylation. Conclusions. This study demonstrates that doxazosin induces apoptosis in PTEN-positive AI PC cells, at least partially, via Akt deactivation and that over-expression of Bcl-2 or AR increases cell resistance to the drug. These results imply that translational potential of doxazosin depends on phenotypic characteristics of PC cells and provide evidence for limitations to its application in hormone refractory tumors

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

Lack of CD151/integrin alpha 3 beta 1 complex is predictive of poor outcome in node-negative lobular breast carcinoma: opposing roles of CD151 in invasive lobular and ductal breast cancers

background: The proposed involvement of CD151 in breast cancer (BCa) progression is based on findings from studies in invasive ductal carcinoma (IDC). The IDC and invasive lobular carcinoma (ILC) represent distinct disease entities. Here we evaluated clinical significance of CD151 alone and in association with integrin α3β1 in patients with ILC in context of the data of our recent IDC study. methods: Expression of CD151 and/or integrin α3β1 was evaluated in ILC samples (N=117) using immunohistochemistry. The findings were analysed in relation to our results from an IDC cohort (N=182) demonstrating a prognostic value of an expression of CD151/integrin α3β1 complex in patients with HER2-negative tumours. results: Unlike in the IDCs, neither CD151 nor CD151/α3β1 complex showed any correlation with any of the ILC characteristics. Lack of both CD151 and α3β1 was significantly correlated with poor survival (P=0.034) in lymph node-negative ILC N(−) cases. The CD151−/α3β1− patients had 3.12-fold higher risk of death from BCa in comparison with the rest of the ILC N(−) patients. conclusions: Biological role of CD151/α3β1 varies between ILC and IDC. Assessment of CD151/α3β1 might help to identify ILC N(−) patients with increased risk of distant metastases

Comprehensive lung injury pathology induced by mTOR inhibitors

Molecular Targets in Oncology[Abstract] Interstitial lung disease is a rare side effect of temsirolimus treatment in renal cancer patients. Pulmonary fibrosis is characterised by the accumulation of extracellular matrix collagen, fibroblast proliferation and migration, and loss of alveolar gas exchange units. Previous studies of pulmonary fibrosis have mainly focused on the fibro-proliferative process in the lungs. However, the molecular mechanism by which sirolimus promotes lung fibrosis remains elusive. Here, we propose an overall cascade hypothesis of interstitial lung diseases that represents a common, partly underlying synergism among them as well as the lung pathogenesis side effects of mammalian target of rapamycin inhibitors

Emotion perception improvement following high frequency transcranial random noise stimulation of the inferior frontal cortex.

Facial emotion perception plays a key role in interpersonal communication and is a precursor for a variety of socio-cognitive abilities. One brain region thought to support emotion perception is the inferior frontal cortex (IFC). The current study aimed to examine whether modulating neural activity in the IFC using high frequency transcranial random noise stimulation (tRNS) could enhance emotion perception abilities. In Experiment 1, participants received either tRNS to IFC or sham stimulation prior to completing facial emotion and identity perception tasks. Those receiving tRNS significantly outperformed those receiving sham stimulation on facial emotion, but not identity, perception tasks. In Experiment 2, we examined whether baseline performance interacted with the effects of stimulation. Participants completed a facial emotion and identity discrimination task prior to and following tRNS to either IFC or an active control region (area V5/MT). Baseline performance was a significant predictor of emotion discrimination performance change following tRNS to IFC. This effect was not observed for tRNS targeted at V5/MT or for identity discrimination. Overall, the findings implicate the IFC in emotion processing and demonstrate that tRNS may be a useful tool to modulate emotion perception when accounting for individual differences in factors such as baseline task performance

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