88 results found
Bevan CL, 2021, Breaking down walls in prostate cancer with the MURAL collection of patient-derived xenografts, NATURE COMMUNICATIONS, Vol: 12
Leach DA, Brooke GN, Bevan CL, 2021, Roles of steroid receptors in the lung and COVID-19., Essays Biochem
COVID-19 symptoms and mortality are largely due to its devastating effects in the lungs. The disease is caused by the SARS (Severe Acute Respiratory Syndrome)-CoV-2 coronavirus, which requires host cell proteins such as ACE2 (angiotensin-converting enzyme 2) and TMPRSS2 (transmembrane serine protease 2) for infection of lung epithelia. The expression and function of the steroid hormone receptor family is important in many aspects that impact on COVID-19 effects in the lung - notably lung development and function, the immune system, and expression of TMPRSS2 and ACE2. This review provides a brief summary of current knowledge on the roles of the steroid hormone receptors [androgen receptor (AR), glucocorticoid receptor (GR), progesterone receptor (PR), mineralocorticoid receptor (MR) and oestrogen receptor (ER)] in the lung, their effects on host cell proteins that facilitate SARS-CoV-2 uptake, and provides a snapshot of current clinical trials investigating the use of steroid receptor (SR) ligands to treat COVID-19.
Leach DA, Mohr A, Giotis ES, et al., 2021, The antiandrogen enzalutamide downregulates TMPRSS2 and reduces cellular entry of SARS-CoV-2 in human lung cells, Nature Communications, Vol: 12, Pages: 1-12, ISSN: 2041-1723
SARS-CoV-2 attacks various organs, most destructively the lung, and cellular entry requires two host cell surface proteins: ACE2 and TMPRSS2. Downregulation of one or both of these is thus a potential therapeutic approach for COVID-19. TMPRSS2 is a known target of the androgen receptor, a ligand-activated transcription factor; androgen receptor activation increases TMPRSS2 levels in various tissues, most notably prostate. We show here that treatment with the antiandrogen enzalutamide – a well-tolerated drug widely used in advanced prostate cancer – reduces TMPRSS2 levels in human lung cells and in mouse lung. Importantly, antiandrogens significantly reduced SARS-CoV-2 entry and infection in lung cells. In support of this experimental data, analysis of existing datasets shows striking co-expression of AR and TMPRSS2, including in specific lung cell types targeted by SARS-CoV-2. Together, the data presented provides strong evidence to support clinical trials to assess the efficacy of antiandrogens as a treatment option for COVID-19.
Lovell S, Zhang L, Kryza T, et al., 2021, A suite of activity-based probes to dissect the KLK activome in drug-resistant prostate cancer, Journal of the American Chemical Society, Vol: 143, Pages: 8911-8924, ISSN: 0002-7863
Kallikrein-related peptidases (KLKs) are a family of secreted serine proteases, which form a network (the KLK activome) with an important role in proteolysis and signaling. In prostate cancer (PCa), increased KLK activity promotes tumor growth and metastasis through multiple biochemical pathways, and specific quantification and tracking of changes in the KLK activome could contribute to validation of KLKs as potential drug targets. Herein we report a technology platform based on novel activity-based probes (ABPs) and inhibitors enabling simultaneous orthogonal analysis of KLK2, KLK3, and KLK14 activity in hormone-responsive PCa cell lines and tumor homogenates. Importantly, we identifed a significant decoupling of KLK activity and abundance and suggest that KLK proteolysis should be considered as an additional parameter, along with the PSA blood test, for accurate PCa diagnosis and monitoring. Using selective inhibitors and multiplexed fluorescent activity-based protein profiling (ABPP), we dissect the KLK activome in PCa cells and show that increased KLK14 activity leads to a migratory phenotype. Furthermore, using biotinylated ABPs, we show that active KLK molecules are secreted into the bone microenvironment by PCa cells following stimulation by osteoblasts suggesting KLK-mediated signaling mechanisms could contribute to PCa metastasis to bone. Together our findings show that ABPP is a powerful approach to dissect dysregulation of the KLK activome as a promising and previously underappreciated therapeutic target in advanced PCa.
Cai S, Pataillot-Meakin T, Shibakawa A, et al., 2021, Single-molecule amplification-free multiplexed detection of circulating microRNA cancer biomarkers from serum, Nature Communications, Vol: 12, ISSN: 2041-1723
MicroRNAs (miRNAs) play essential roles in post-transcriptional gene expression and are also found freely circulating in bodily fluids such as blood. Dysregulated miRNA signatures have been associated with many diseases including cancer, and miRNA profiling from liquid biopsies offers a promising strategy for cancer diagnosis, prognosis and monitoring. Here, we develop size-encoded molecular probes that can be used for simultaneous electro-optical nanopore sensing of miRNAs, allowing for ultrasensitive, sequence-specific and multiplexed detection directly in unprocessed human serum, in sample volumes as small as 0.1 μl. We show that this approach allows for femtomolar sensitivity and single-base mismatch selectivity. We demonstrate the ability to simultaneously monitor miRNAs (miR-141-3p and miR-375-3p) from prostate cancer patients with active disease and in remission. This technology can pave the way for next generation of minimally invasive diagnostic and companion diagnostic tests for cancer.
Blanquart E, Mandonnet A, Mars M, et al., 2021, Targeting androgen signaling in ILC2s protects from IL-33-driven lung inflammation, independently of KLRG1., J Allergy Clin Immunol
BACKGROUND: Allergic asthma is more severe and frequent in women than in men. In male mice, androgens negatively control group 2 innate lymphoid cell (ILC2) development and function by yet unknown mechanisms. OBJECTIVES: We sought to investigate the impact of androgen on ILC2 homeostasis and IL-33-mediated inflammation in female lungs. We evaluated the role of androgen receptor (AR) signaling and the contribution of the putative inhibitory receptor killer cell lectin-like receptor G1 (KLRG1). METHODS: Subcutaneous pellets mimicking physiological levels of androgen were used to treat female mice together with mice expressing a reporter enzyme under the control of androgen response elements and mixed bone marrow chimeras to assess the cell-intrinsic role of AR activation within ILC2s. We generated KLRG1-deficient mice. RESULTS: We established that lung ILC2s express a functionally active AR that can be in vivo targeted with exogenous androgens to negatively control ILC2 homeostasis, proliferation, and function. Androgen signaling upregulated KLRG1 on ILC2s, which inhibited their proliferation on E-cadherin interaction. Despite evidence that KLRG1 impaired the competitive fitness of lung ILC2s during inflammation, KLRG1 deficiency neither alters in vivo ILC2 numbers and functions, nor did it lead to hyperactive ILC2s in either sexes. CONCLUSIONS: AR agonists can be used in vivo to inhibit ILC2 homeostatic numbers and ILC2-dependent lung inflammation through cell-intrinsic AR activation. Although androgen signals in ILC2s to upregulate KLRG1, we demonstrate that KLRG1 is dispensable for androgen-mediated inhibition of pulmonary ILC2s.
Oduwole OO, Poliandri A, Okolo A, et al., 2021, Follicle-stimulating hormone promotes growth of human prostate cancer cell line-derived tumor xenografts, FASEB JOURNAL, Vol: 35, ISSN: 0892-6638
Estebanez-Perpina E, Bevan CL, McEwan IJ, 2021, Eighty years of targeting androgen receptor activity in prostate cancer: the fight goes on, Cancers, Vol: 13, Pages: 1-19, ISSN: 2072-6694
Prostate cancer (PCa) is the most common cancer in men in the West, other than skin cancer, accounting for over a quarter of cancer diagnoses in US men. In a seminal paper from 1941, Huggins and Hodges demonstrated that prostate tumours and metastatic disease were sensitive to the presence or absence of androgenic hormones. The first hormonal therapy for PCa was thus castration. In the subsequent eighty years, targeting the androgen signalling axis, where possible using drugs rather than surgery, has been a mainstay in the treatment of advanced and metastatic disease. Androgens signal via the androgen receptor, a ligand-activated transcription factor, which is the direct target of many such drugs. In this review we discuss the role of the androgen receptor in PCa and how the combination of structural information and functional screenings is continuing to be used for the discovery of new drug to switch off the receptor or modify its function in cancer cells.
Siddappa M, Wani SA, Long MD, et al., 2020, Identification of transcription factor co-regulators that drive prostate cancer progression, Scientific Reports, Vol: 10, Pages: 1-16, ISSN: 2045-2322
In prostate cancer (PCa), and many other hormone-dependent cancers, there is clear evidence for distorted transcriptional control as disease driver mechanisms. Defining which transcription factor (TF) and coregulators are altered and combine to become oncogenic drivers remains a challenge, in part because of the multitude of TFs and coregulators and the diverse genomic space on which they function. The current study was undertaken to identify which TFs and coregulators are commonly altered in PCa. We generated unique lists of TFs (n = 2662), coactivators (COA; n = 766); corepressors (COR; n = 599); mixed function coregulators (MIXED; n = 511), and to address the challenge of defining how these genes are altered we tested how expression, copy number alterations and mutation status varied across seven prostate cancer (PCa) cohorts (three of localized and four advanced disease). Testing of significant changes was undertaken by bootstrapping approaches and the most significant changes were identified. For one commonly and significantly altered gene were stably knocked-down expression and undertook cell biology experiments and RNA-Seq to identify differentially altered gene networks and their association with PCa progression risks. COAS, CORS, MIXED and TFs all displayed significant down-regulated expression (q.value < 0.1) and correlated with protein expression (r 0.4–0.55). In localized PCa, stringent expression filtering identified commonly altered TFs and coregulator genes, including well-established (e.g. ERG) and underexplored (e.g. PPARGC1A, encodes PGC1α). Reduced PPARGC1A expression significantly associated with worse disease-free survival in two cohorts of localized PCa. Stable PGC1α knockdown in LNCaP cells increased growth rates and invasiveness and RNA-Seq revealed a profound basal impact on gene expression (~ 2300 genes; FDR < 0.05, logFC&thins
Jarvis S, Gethings LA, Samanta L, et al., 2020, High fat diet causes distinct aberrations in the testicular proteome, International Journal of Obesity, Vol: 44, Pages: 1958-1969, ISSN: 0307-0565
Diet has important effects on normal physiology and the potential deleterious effects of high fat diets and obesity on male reproductive health are being increasingly described. We conducted a histological review of the effects of chronic high fat (HF) diet (using a mouse model fed a 45% fat diet for 21 weeks) with a discovery proteomic study to assess for changes in the abundance of proteins in the testis. Mice on a HF diet became obese and developed glucose intolerance. Using mass spectrometry, we identify 102 proteins affected in the testis of obese mice. These included structural proteins important for the blood testis barrier (filamin A, FLNA), proteins involved in oxidative stress responses (spermatogenesis associated 20, SPATA-20) and lipid homoeostasis (sterol regulatory element-binding protein 2, SREBP2 and apolipoprotein A1, APOA1). In addition, an important regulator protein paraspeckle component 1, PSPC-1, which interacts with the androgen receptor was significantly downregulated. Proteomic data was validated using both Western blotting and immunostaining which confirmed and localised protein expression in both mouse and human testis using biopsy specimens. This study focused mainly on the abnormalities that occurred at the protein level and as a result, we have identified several candidate proteins and conducted pathway analysis around the effects of HF diet on the testis providing novel insights not previously described. Some of the identified targets could be targeted therapeutically and future work is directed in this area.
Eringyte I, Zamarbide Losada JN, Powell SM, et al., 2020, Coordinated AR and microRNA regulation in prostate cancer, Asian Journal of Urology, Vol: 7, Pages: 233-250, ISSN: 2214-3882
The androgen receptor (AR) remains a key driver of prostate cancer (PCa) progression, even in the advanced castrate-resistant stage, where testicular androgens are absent. It is therefore of critical importance to understand the molecular mechanisms governing its activity and regulation during prostate tumourigenesis. MicroRNAs (miRs) are small ∼22 nt non-coding RNAs that regulate target gene, often through association with 3' untranslated regions (3'UTRs) of transcripts. They display dysregulation during cancer progression, can function as oncogenes or tumour suppressors, and are increasingly recognised as targets or regulators of hormonal action. Thus, understanding factors which modulate miRs synthesis is essential. There is increasing evidence for complex and dynamic bi-directional cross-talk between the multi-step miR biogenesis cascade and the AR signalling axis in PCa. This review summarises the wealth of mechanisms by which miRs are regulated by AR, and conversely, how miRs impact AR's transcriptional activity, including that of AR splice variants. In addition, we assess the implications of the convergence of these pathways on the clinical employment of miRs as PCa biomarkers and therapeutic targets.
Connor MJ, Shah TT, Horan G, et al., 2020, Cytoreductive treatment strategies for de novo metastatic prostate cancer, NATURE REVIEWS CLINICAL ONCOLOGY, Vol: 17, Pages: 168-182, ISSN: 1759-4774
Kalofonou F, Sita-Lumsden A, Leach D, et al., 2020, MiR-27a-3p: An AR-modulatory microRNA with a distinct role in prostate cancer progression and therapy, Genitourinary Cancers Symposium of the American-Society-of-Clinical-Oncology (ASCO), Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X
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, Pages: 1-6, 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.
Fletcher CE, Godfrey JD, Shibakawa A, et al., 2017, 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...
Sita-Lumsden AR, Leach D, Zivi A, et al., 2017, A circulating miRNA signature to help prognosticate at prostate cancer diagnosis., ASCO Genitourinary Cancers Symposium, 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 ...
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.