74 results found
Jarvis S, Williamson C, Bevan C, 2019, Liver X receptors and male (in)fertility, International Journal of Molecular Sciences, Vol: 20, ISSN: 1422-0067
Liver X receptors (LXRs) are ligand-dependent transcription factors acting as ‘cholesterol sensors’ to regulate lipid homeostasis in cells. The two isoforms, LXRα (NR1H3) and LXRβ (NR1H2), are differentially expressed, with the former expressed predominantly in metabolically active tissues and the latter more ubiquitously. Both are activated by oxidised cholesterol metabolites, endogenously produced oxysterols. LXRs have important roles in lipid metabolism and inflammation, plus a number of newly emerging roles. They are implicated in regulating lipid balance in normal male reproductive function and may provide a link between male infertility and lipid disorders and/or obesity. Studies from Lxr knockout mouse models provide compelling evidence to support this. More recently published data suggest distinct and overlapping roles of the LXR isoforms in the testis and recent evidence of a role for LXRs in human male fertility. This review summarises the current literature and explores the likely link between LXR, lipid metabolism and male fertility as part of a special issue on Liver X receptors in International Journal of Molecular Sciences.
Hindley JW, Zheleva DG, Elani Y, et al., 2019, Building a synthetic mechanosensitive signaling pathway in compartmentalized artificial cells, Proceedings of the National Academy of Sciences, Vol: 116, Pages: 16711-16716, ISSN: 0027-8424
To date reconstitution of one of the fundamental methods of cell communication, the signaling pathway, has been unaddressed in the bottom-up construction of artificial cells (ACs). Such developments are needed to increase the functionality and biomimicry of ACs, accelerating their translation and application in biotechnology. Here we report the construction of a de novo synthetic signaling pathway in microscale nested vesicles. Vesicle cell models respond to external calcium signals through activation of an intracellular interaction between phospholipase A2 and a mechanosensitive channel present in the internal membranes, triggering content mixing between compartments and controlling cell fluorescence. Emulsion-based approaches to AC construction are therefore shown to be ideal for the quick design and testing of new signaling networks and can readily include synthetic molecules difficult to introduce to biological cells. This work represents a foundation for the engineering of multi-compartment-spanning designer pathways that can be utilised to control downstream events inside an artificial cell, leading to the assembly of micromachines capable of sensing and responding to changes in their local environment.
Fletcher C, Sulpice E, Combe S, et al., 2019, Androgen receptor-modulatory microRNAs provide insight into therapy resistance and therapeutic targets in advanced prostate cancer, Oncogene, Vol: 38, Pages: 5700-5724, ISSN: 0950-9232
Androgen receptor (AR) signalling is a key prostate cancer (PC) driver, even inadvanced ‘castrate-resistant’ disease (CRPC). To systematically identify microRNAs (miRs) modulating AR activity in lethal disease, hormone-responsive and -resistant PC cells expressing a luciferase-based AR reporter were transfected with a miR inhibitor library; 78 inhibitors significantly altered AR activity. Upon validation, miR-346, miR-361-3p and miR-197 inhibitors dramatically reduced AR transcriptional activity, mRNA and protein levels, increased apoptosis, reduced proliferation, repressed EMT, inhibited PC migration and invasion, demonstrating additive effects with AR inhibition. Corresponding miRs increased AR activity through a novel and anti-dogmatic mechanism of direct association with AR 6.9kb 3’UTR and transcript stabilisation. In addition, miR-346 and miR-361-3p modulation altered levels of constitutively-active AR variants, and inhibited variant-driven PC cell proliferation, so may contribute to persistent AR signalling in CRPC in the absence of circulating androgens. Pathway analysis of AGO-PAR-CLIP-identified miR targets revealed roles in DNA replication and repair, cell cycle, signal transduction and immune function. Silencing these targets, including tumour suppressors ARHGDIA and TAGLN2, phenocopied miR effects, demonstrating physiological relevance. MiR-346 additionally upregulated the oncogene, YWHAZ, which correlated with grade, biochemical relapse and metastasis in patients. These AR-modulatory miRs and targets correlated with AR activity in patient biopsies, and were elevated in response to long-term enzalutamide treatment of patient-derived CRPC xenografts. In summary, we identified miRs that modulate AR activity in PC and CRPC, via novel mechanisms, and may represent novel PC the
Kalofonou F, Leach D, Hamilton M, et al., 2019, MiR-1271-5p: An AR-modulatory microRNA with a distinct role in prostate cancer progression, through SND1 and MORF4L1 interaction., Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X
Wang C, Datoo T, Zhao H, et al., 2018, Midazolam and Dexmedetomidine Affect Neuroglioma and Lung Carcinoma Cell Biology In Vitro and In Vivo, ANESTHESIOLOGY, Vol: 129, Pages: 1000-1014, ISSN: 0003-3022
Dart DA, Kandil S, Tommasini-Ghelfi S, et al., 2018, Novel trifluoromethylated enobosarm analogues with potent anti-androgenic activity in vitro and tissue selectivity in vivo, Molecular Cancer Therapeutics, Vol: 17, Pages: 1846-1858, ISSN: 1535-7163
Prostate cancer often develops anti-androgen resistance, possibly via androgen receptor (AR) mutations which change antagonists to agonists. Novel therapies with increased anticancer activity, whilst overcoming current drug resistance are urgently needed. Enobosarm has anabolic effects on muscle and bone whilst having no effect on the prostate. Here we describe the activity of novel chemically modified enobosarm analogues. The rational addition of bis-trifluoromethyl groups into ring B of enobosarm, profoundly modified their activity, pharmacokinetic and tissue distribution profiles. These chemical structural modifications resulted in an improved AR binding affinity - by increasing the molecular occupational volume near helix 12 of AR. In vitro, the analogues SK33 and SK51 showed very potent antiandrogenic activity, monitored using LNCaP/AR-Luciferase cells where growth, PSA and luciferase activity were used as AR activity measurements. These compounds were 10-fold more potent than bicalutamide and 100-fold more potent than enobosarm within the LNCaP model. These compounds were also active in LNCaP/BicR cells with acquired bicalutamide resistance. In vivo, using the AR-Luc reporter mice, these drugs showed potent AR inhibitory activity in the prostate and other AR-expressing tissues e.g. testes, seminal vesicles and brain. These compounds do not inhibit AR activity in the skeletal muscle, and spleen - thus indicating a selective tissue inhibitory profile. These compounds were also active in vivo in the Pb-PTen deletion model. SK33 and SK51 have significantly different and enhanced activity profiles compared to enobosarm, and are ideal candidates for further development for prostate cancer therapy with potentially fewer side effects.
Sumanasuriya S, Omlin A, Armstrong A, et al., 2018, Consensus Statement on Circulating Biomarkers for Advanced Prostate Cancer, European Urology Oncology, Vol: 1, Pages: 151-159, ISSN: 2588-9311
Luo J, Attard G, Balk SP, et al., 2018, Role of androgen receptor variants in prostate cancer: Report from the 2017 Mission Androgen Receptor Variants Meeting, European Urology, Vol: 73, Pages: 715-723, ISSN: 0302-2838
CONTEXT: Although a number of studies have demonstrated the importance of constitutively active androgen receptor variants (AR-Vs) in prostate cancer, questions still remain about the precise role of AR-Vs in the progression of castration-resistant prostate cancer (CRPC). OBJECTIVE: Key stakeholders and opinion leaders in prostate cancer convened on May 11, 2017 in Boston to establish the current state of the field of AR-Vs. EVIDENCE ACQUISITION: The meeting "Mission Androgen Receptor Variants" was the second of its kind sponsored by the Prostate Cancer Foundation (PCF). This invitation-only event was attended by international leaders in the field and representatives from sponsoring organizations (PCF and industry sponsors). Eighteen faculty members gave short presentations, which were followed by in-depth discussions. Discussions focused on three thematic topics: (1) potential of AR-Vs as biomarkers of therapeutic resistance; (2) role of AR-Vs as functionally active CRPC progression drivers; and (3) utility of AR-Vs as therapeutic targets in CRPC. EVIDENCE SYNTHESIS: The three meeting organizers synthesized this meeting report, which is intended to summarize major data discussed at the meeting and identify key questions as well as strategies for addressing these questions. There was a critical consensus that further study of the AR-Vs is an important research focus in CRPC. Contrasting views and emphasis, each supported by data, were presented at the meeting, discussed among the participants, and synthesized in this report. CONCLUSIONS: This article highlights the state of knowledge and outlines the most pressing questions that need to be addressed to advance the AR-V field. PATIENT SUMMARY: Although further investigation is needed to delineate the role of androgen receptor (AR) variants in metastatic castration-resistant prostate cancer, advances in measurement science have enabled development of blood-based tests for treatment selection. Detection of AR
Hindley JW, Elani Y, McGilvery CM, et al., 2018, Light-triggered enzymatic reactions in nested vesicle reactors, Nature Communications, Vol: 9, ISSN: 2041-1723
Cell-sized vesicles have tremendous potential both as miniaturised pL reaction vessels and in bottom-up synthetic biology as chassis for artificial cells. In both these areas the introduction of light-responsive modules affords increased functionality, for example, to initiate enzymatic reactions in the vesicle interior with spatiotemporal control. Here we report a system composed of nested vesicles where the inner compartments act as phototransducers, responding to ultraviolet irradiation through diacetylene polymerisation-induced pore formation to initiate enzymatic reactions. The controlled release and hydrolysis of a fluorogenic β-galactosidase substrate in the external compartment is demonstrated, where the rate of reaction can be modulated by varying ultraviolet exposure time. Such cell-like nested microreactor structures could be utilised in fields from biocatalysis through to drug delivery.
Sumanasuriya S, Omlin AG, Armstrong AJ, et al., 2018, Consensus statement on circulating biomarkers for advanced prostate cancer., Genitourinary Cancers Symposium, Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X
Sita-Lumsden AR, Sita-Lumsden AR, Leach D, et al., 2017, A circulating miRNA signature to better stratify prostate cancer patients at diagnosis, 19th National Congress of Medical Oncology, Publisher: OXFORD UNIV PRESS, ISSN: 0923-7534
Gethings LA, Richardson K, Wildgoose J, et al., 2017, Lipid profiling of complex biological mixtures by liquid chromatography/mass spectrometry using a novel scanning quadrupole data-independent acquisition strategy, Rapid Communications in Mass Spectrometry, Vol: 31, Pages: 1599-1606, ISSN: 0951-4198
RationaleA novel data-independent acquisition method is detailed that incorporates a scanning quadrupole in front of an orthogonal acceleration time-of-flight (TOF) mass analyser. This approach is described and the attributes are compared and contrasted to other DIA approaches.MethodsSpecific application of the method to both targeted and untargeted lipidomic identification strategies is discussed, with data from both shotgun and LC separated lipidomics experiments presented.ResultsThe benefits of the fast quadrupole scanning technique are highlighted, and include improvements in speed and specificity for complex mixtures providing high quality qualitative and quantitative data.ConclusionsIn particular the high specificity afforded by the scanning quadrupole improves qualitative information for lipid identification.
Sita-Lumsden AR, Leach D, Zivi A, et al., 2017, A signature of miRNAs in the blood to help prognosticate prostate cancer at the time of diagnosis., 53rd Annual Clinical Meeting of the American-Society-of-Clinical-Oncology (ASCO), Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X
Koushyar S, Economides G, Zaat S, et al., 2017, The prohibitin-repressive interaction with E2F1 is rapidly inhibited by androgen signalling in prostate cancer cells, Oncogenesis, Vol: 6, ISSN: 2157-9024
Prohibitin (PHB) is a tumour suppressor molecule with pleiotropic activities across several cellular compartments including mitochondria, cell membrane and the nucleus. PHB and the steroid-activated androgen receptor (AR) have an interplay where AR downregulates PHB, and PHB represses AR. Additionally, their cellular locations and chromatin interactions are in dynamic opposition. We investigated the mechanisms of cell cycle inhibition by PHB and how this is modulated by AR in prostate cancer. Using a prostate cancer cell line overexpressing PHB, we analysed the gene expression changes associated with PHB-mediated cell cycle arrest. Over 1000 gene expression changes were found to be significant and gene ontology analysis confirmed PHB-mediated repression of genes essential for DNA replication and synthesis, for example, MCMs and TK1, via an E2F1 regulated pathway-agreeing with its G1/S cell cycle arrest activity. PHB is known to inhibit E2F1-mediated transcription, and the PHB:E2F1 interaction was seen in LNCaP nuclear extracts, which was then reduced by androgen treatment. Upon two-dimensional western blot analysis, the PHB protein itself showed androgen-mediated charge differentiation (only in AR-positive cells), indicating a potential dephosphorylation event. Kinexus phosphoprotein array analysis indicated that Src kinase was the main interacting intracellular signalling hub in androgen-treated LNCaP cells, and that Src inhibition could reduce this AR-mediated charge differentiation. PHB charge change may be associated with rapid dissociation from chromatin and E2F1, allowing the cell cycle to proceed. The AR and androgens may deactivate the repressive functions of PHB upon E2F1 leading to cell cycle progression, and indicates a role for AR in DNA replication licensing.
Sita-Lumsden AR, Leach D, Zivi A, et al., 2017, A circulating miRNA signature to help prognosticate at prostate cancer diagnosis., Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X
Bevan C, 2016, Women in cancer profile: A gender agenda?, Endocrine-Related Cancer, Vol: 23, Pages: P5-P8, ISSN: 1479-6821
Extract: Growing up, I never understood why so many people professed to have no interest in science. How could understanding how things work not be the most fascinating thing? And how we, as organisms, develop and function (or fail to) seemed to me the most fascinating thing of all. One of my most inspiring school teachers was the head of Biology and 6th-form, Dr Chris Haworth, who undertook to nurture my ambition to gain a place at "Oxbridge" (no-one from our comprehensive school in the far north of England had previously gone to either Cambridge or Oxford). I remember one lesson we came in to find dandelion leaves strewn around the room. It turned out they were all different, representing a fair proportion of the 250-odd species of dandelion on which, had I but appreciated it at the time, Dr Haworth was a recognised authority. While many of my classmates flatly refused to see any difference between the leaves, it was my first introduction to genetic diversity. And speaking of diversity, I wanted to keep my options open so crammed in as many A level subjects as I could, from Applied Mathematics to English Literature, refusing to drop any despite the recommendations by careers advisers and admissions tutors ...
Bevan CL, Fletcher CE, Godfrey JD, et al., 2016, A novel role for GSK3β as a modulator of Drosha microprocessor activity and MicroRNA biogenesis, Nucleic Acid Research, Vol: 45, Pages: 2809-2828, ISSN: 2159-3345
Regulation of microRNA (miR) biogenesis is complex and stringently controlled. Here, we identify the kinase GSK3ß as a important modulator of miR biogenesis at Microprocessor level. Repression of GSK3ß activity reduces Drosha activity towards pri-miRs, leading to accumulation of unprocessed pri-miRs and reduction of mature pri-miRs without altering levels or cellular locations of miR biogenesis proteins...
Leach DA, Powell SM, Bevan C, 2016, New roles for nuclear receptors in prostate cancer, Endocrine-Related Cancer, Vol: 23, Pages: T85-T108, ISSN: 1479-6821
Prostate cancer has, for decades, been treated by inhibiting androgen signalling. This is effective in the majority of patients, but inevitably resistance develops and patients progress to life-threatening metastatic disease - hence the quest for new effective therapies for "castrate-resistant" prostate cancer (CRPC). Studies into what pathways can drive tumour recurrence under these conditions has identified several other nuclear receptor signalling pathways as potential drivers or modulators of CRPC. The nuclear receptors constitute a large (48 members) superfamily of transcription factors sharing a common modular functional structure. Many of them are activated by the binding of small lipophilic molecules, making them potentially druggable. Even those for which no ligand exists or has yet been identified may be tractable to activity modulation by small molecules. Moreover, genomic studies have shown that in models of CRPC other nuclear receptors can potentially drive similar transcriptional responses to the androgen receptor, while analysis of expression and sequencing databases shows disproportionately high mutation and copy number variation rates among the superfamily. Hence the nuclear receptor superfamily is of intense interest in the drive to understand how prostate cancer recurs and how we may best treat such recurrent disease. This reviews aims to provide a snapshot of current knowledge of the roles of different nuclear receptors in prostate cancer, a rapidly-evolving field of research.
Leach DA, Panagopoulos V, Nash C, et al., 2016, Cell-lineage specificity and role of AP-1 in the prostate fibroblast androgen receptor cistrome., Molecular and Cellular Endocrinology, Vol: 439, Pages: 261-272, ISSN: 1872-8057
Androgen receptor (AR) signalling in fibroblasts is important in prostate development and carcinogenesis, and is inversely related to prostate cancer mortality. However, the molecular mechanisms of AR action in fibroblasts and other non-epithelial cell types are largely unknown. The genome-wide DNA binding profile of AR in human prostate fibroblasts was identified by chromatin immunoprecipitation sequencing (ChIP-Seq), and found to be common to other fibroblast lines but disparate from AR cistromes of prostate cancer cells and tissue. Although AR binding sites specific to fibroblasts were less well conserved evolutionarily than those shared with cancer epithelia, they were likewise correlated with androgen regulation of fibroblast gene expression. Whereas FOXA1 is the key pioneer factor of AR in cancer epithelia, our data indicated that AP-1 likely plays a more important role in the AR cistrome in fibroblasts. The specificity of AP-1 and FOXA1 to binding in these cells is demonstrated using immunoblot and immunohistochemistry. Importantly, we find the fibroblast cistrome is represented in whole tissue/in vivo ChIP-seq studies at both genomic and resulting protein levels, highlighting the importance of the stroma in whole tissue -omic studies. This is the first nuclear receptor ChIP-seq study in prostatic fibroblasts, and provides novel insight into the action of fibroblast AR in prostate cancer.
Metcalf GAD, Shibakawa A, Patel H, et al., 2016, Amplification-Free Detection of Circulating microRNA Biomarkers from Body Fluids Based on Fluorogenic Oligonucleotide-Templated Reaction between Engineered Peptide Nucleic Acid Probes: Application to Prostate Cancer Diagnosis, Analytical Chemistry, Vol: 88, Pages: 8091-8098, ISSN: 1086-4377
Highly abundant in cells, microRNAs (or miRs) play a key role as regulators of gene expression. A proportion of them are also detectable in biofluids making them ideal noninvasive biomarkers for pathologies in which miR levels are aberrantly expressed, such as cancer. Peptide nucleic acids (PNAs) are engineered uncharged oligonucleotide analogues capable of hybridizing to complementary nucleic acids with high affinity and high specificity. Herein, novel PNA-based fluorogenic biosensors have been designed and synthesized that target miR biomarkers for prostate cancer (PCa). The sensing strategy is based on oligonucleotide-templated reactions where the only miR of interest serves as a matrix to catalyze an otherwise highly unfavorable fluorogenic reaction. Validated in vitro using synthetic RNAs, these newly developed biosensors were then shown to detect endogenous concentrations of miR in human blood samples without the need for any amplification step and with minimal sample processing. This low-cost, quantitative, and versatile sensing technology has been technically validated using gold-standard RT-qPCR. Compared to RT-qPCR however, this enzyme-free, isothermal blood test is amenable to incorporation into low-cost portable devices and could therefore be suitable for widespread public screening.
Pine AC, Fioretti FF, Brooke GN, et al., 2016, Advances in genetics: widening our understanding of prostate cancer, F1000 Research, Vol: 5, ISSN: 2046-1402
Prostate cancer is a leading cause of cancer-related death in Western men. Our understanding of the genetic alterations associated with disease predisposition, development, progression, and therapy response is rapidly improving, at least in part, owing to the development of next-generation sequencing technologies. Large advances have been made in our understanding of the genetics of prostate cancer through the application of whole-exome sequencing, and this review summarises recent advances in this field and discusses how exome sequencing could be used clinically to promote personalised medicine for prostate cancer patients.
Dart DA, Bevan CL, 2016, In Vivo Imaging of Nuclear Receptor Transcriptional Activity., Publisher: Humana Press, ISBN: 978-1-4939-3722-6
Nuclear receptors drive key processes during development, reproduction, metabolism, and disease. In order to understand and analyze, as well as manipulate, their actions it is imperative that we are able to study them in whole animals and in a spatiotemporal manner. The increasing repertoire of transgenic animals, expressing reporter genes driven by a specific nuclear receptor, enables us to do this. Use of luciferase reporter genes is the method of choice of many researchers as it is well tolerated, relatively easy to use, and robust. Further, luciferase lends itself to the process as it can penetrate tissue and can be manipulated to degrade rapidly thus allowing a dynamic response. However, limited resolution, lack of quantitation, and the largely two-dimensional images acquired make it desirable to support results using ex vivo imaging and enzymatic and/or immunohistochemical analysis of dissected tissue. As well as enabling the visualization of nuclear receptor signaling in wild-type animals, crossing these mouse models with models of disease will provide invaluable information on how such signaling is dysregulated during disease progression, and how we may manipulate nuclear receptor signaling in therapy. The use of in vivo imaging therefore provides the power to determine where and when in development, aging, and disease nuclear receptors are active and how ligands or receptor modulators affect this.
Fletcher CE, Bevan CL, Sita-Lumsden A, et al., 2015, Circulating Nucleic Acids as Prostate Cancer Biomarkers, Epigenetic Biomarkers and Diagnostics, Editors: Garcia-Giménez, Publisher: Elsevier
Brooke GN, Gamble SC, Hough MA, et al., 2015, Antiandrogens act as selective androgen receptor modulators at the proteome Level in prostate cancer cells, Molecular & Cellular Proteomics, Vol: 14, Pages: 1201-1216, ISSN: 1535-9484
Current therapies for prostate cancer include antiandrogens, inhibitory ligands of the androgen receptor, which repress androgen-stimulated growth. These include the selective androgen receptor modulators cyproterone acetate and hydroxyflutamide and the complete antagonist bicalutamide. Their activity is partly dictated by the presence of androgen receptor mutations, which are commonly detected in patients who relapse while receiving antiandrogens, i.e. in castrate-resistant prostate cancer. To characterize the early proteomic response to these antiandrogens we used the LNCaP prostate cancer cell line, which harbors the androgen receptor mutation most commonly detected in castrate-resistant tumors (T877A), analyzing alterations in the proteome, and comparing these to the effect of these therapeutics upon androgen receptor activity and cell proliferation. The majority are regulated post-transcriptionally, possibly via nongenomic androgen receptor signaling. Differences detected between the exposure groups demonstrate subtle changes in the biological response to each specific ligand, suggesting a spectrum of agonistic and antagonistic effects dependent on the ligand used. Analysis of the crystal structures of the AR in the presence of cyproterone acetate, hydroxyflutamide, and DHT identified important differences in the orientation of key residues located in the AF-2 and BF-3 protein interaction surfaces. This further implies that although there is commonality in the growth responses between androgens and those antiandrogens that stimulate growth in the presence of a mutation, there may also be influential differences in the growth pathways stimulated by the different ligands. This therefore has implications for prostate cancer treatment because tumors may respond differently dependent upon which mutation is present and which ligand is activating growth, also for the design of selective androgen receptor modulators, which aim to elicit differential proteomic responses
Cano LQ, Lavery DN, Sin S, et al., 2015, The co-chaperone p23 promotes prostate cancer motility and metastasis, MOLECULAR ONCOLOGY, Vol: 9, Pages: 295-308, ISSN: 1574-7891
Huang H, Benzonana LL, Zhao H, et al., 2014, Prostate cancer cell malignancy via modulation of HIF-1 alpha pathway with isoflurane and propofol alone and in combination, British Journal of Cancer, Vol: 111, Pages: 1338-1349, ISSN: 1532-1827
Background: Surgery is considered to be the first line treatment for solid tumours. Recently, retrospective studies reported thatgeneral anaesthesia was associated with worse long-term cancer-free survival when compared with regional anaesthesia. This hasimportant clinical implications; however, the mechanisms underlying those observations remain unclear. We aim to investigate theeffect of anaesthetics isoflurane and propofol on prostate cancer malignancy.Methods: Prostate cancer (PC3) cell line was exposed to commonly used anaesthetic isoflurane and propofol. Malignant potentialwas assessed through evaluation of expression level of hypoxia-inducible factor-1a (HIF-1a) and its downstream effectors, cellproliferation and migration as well as development of chemoresistance.Results: We demonstrated that isoflurane, at a clinically relevant concentration induced upregulation of HIF-1a and itsdownstream effectors in PC3 cell line. Consequently, cancer cell characteristics associated with malignancy were enhanced, withan increase of proliferation and migration, as well as development of chemoresistance. Inhibition of HIF-1a neosynthesis throughupper pathway blocking by a PI-3K-Akt inhibitor or HIF-1a siRNA abolished isoflurane-induced effects. In contrast, the intravenousanaesthetic propofol inhibited HIF-1a activation induced by hypoxia or CoCl2. Propofol also prevented isoflurane-induced HIF-1aactivation, and partially reduced cancer cell malignant activities.Conclusions: Our findings suggest that modulation of HIF-1a activity by anaesthetics may affect cancer recurrence followingsurgery. If our data were to be extrapolated to the clinical setting, isoflurane but not propofol should be avoided for use in cancersurgery. Further work involving in vivo models and clinical trials is urgently needed to determine the optimal anaesthetic regimenfor cancer patients.
Rudraraju B, Droog M, Abdel-Fatah TMA, et al., 2014, Phosphorylation of activating transcription factor-2 (ATF-2) within the activation domain is a key determinant of sensitivity to tamoxifen in breast cancer, BREAST CANCER RESEARCH AND TREATMENT, Vol: 147, Pages: 295-309, ISSN: 0167-6806
Fletcher CE, Dart DA, Bevan CL, 2014, Interplay between steroid signalling and microRNAs: implications for hormone-dependent cancers, Endocrine-Related Cancer, Vol: 21, Pages: R409-R429, ISSN: 1479-6821
Hormones are key drivers of cancer development. To date, interest has largely been focussed on the classical model of hormonal gene regulation, but there is increasing evidence for a role of hormone signalling pathways in post-translational regulation of gene expression. In particular, a complex and dynamic network of bi-directional interactions with microRNAs (miRs) at all stages of biogenesis and during target gene repression is emerging. miRs, which act mainly by negatively regulating gene expression through association with 3′-UTRs of mRNA species, are increasingly understood to be important in development, normal physiology and pathogenesis. Given recent demonstrations of altered miR profiles in a diverse range of cancers, their ability to function as oncogenes or tumour suppressors, and hormonal regulation of miRs, understanding mechanisms by which miRs are generated and regulated is vitally important. miRs are transcribed by RNA polymerase II and then processed in the nucleus by the Drosha-containing Microprocessor complex and in the cytoplasm by Dicer, before mature miRs are incorporated into the RNA-induced silencing complex. It is increasingly evident that multiple cellular signalling pathways converge upon the miR biogenesis cascade, adding further layers of regulatory complexity to modulate miR maturation. This review summarises recent advances in identification of novel components and regulators of the Microprocessor and Dicer complexes, with particular emphasis on the role of hormone signalling pathways in regulating their activity. Understanding hormone regulation of miR production and how this is perturbed in cancer are critical for the development of miR-based therapeutics and biomarkers.
Fioretti FM, Sita-Lumsden A, Bevan CL, et al., 2014, Revising the role of the androgen receptor in breast cancer, JOURNAL OF MOLECULAR ENDOCRINOLOGY, Vol: 52, Pages: R257-R265, ISSN: 0952-5041
Brooke GN, Powell SM, Lavery DN, et al., 2014, Engineered repressors are potent inhibitors of androgen receptor activity, Oncotarget, Vol: 5, Pages: 959-969, ISSN: 1949-2553
Prostate cancer growth is dependent upon the Androgen Receptor (AR) pathway, hence therapies for this disease often target this signalling axis. Such therapies are successful in the majority of patients but invariably fail after a median of 2 years and tumours progress to a castrate resistant stage (CRPC). Much evidence exists to suggest that the AR remains key to CRPC growth and hence remains a valid therapeutic target. Here we describe a novel method to inhibit AR activity, consisting of an interaction motif, that binds to the AR ligand-binding domain, fused to repression domains. These ‘engineered repressors’ are potent inhibitors of AR activity and prostate cancer cell growth and importantly inhibit the AR under circumstances in which conventional therapies would be predicted to fail, such as AR mutation and altered cofactor levels.
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