196,105 research outputs found
The Contribution of Different Androgen Receptor Domains to Receptor Dimerization and Signaling
No full textThe androgen receptor (AR) is a ligand-activated transcription factor of the nuclear receptor superfamily that plays a critical role in male physiology and pathology. Activated by binding of the native androgens testosterone and 5{alpha}-dihydrotestosterone, the AR regulates transcription of genes involved in the development and maintenance of male phenotype and male reproductive function as well as other tissues such as bone and muscle. Deregulation of AR signaling can cause a diverse range of clinical conditions, including the X-linked androgen insensitivity syndrome, a form of motor neuron disease known as Kennedy’s disease, and male infertility. In addition, there is now compelling evidence that the AR is involved in all stages of prostate tumorigenesis including initiation, progression, and treatment resistance. To better understand the role of AR signaling in the pathogenesis of these conditions, it is important to have a comprehensive understanding of the key determinants of AR structure and function. Binding of androgens to the AR induces receptor dimerization, facilitating DNA binding and the recruitment of cofactors and transcriptional machinery to regulate expression of target genes. Various models of dimerization have been described for the AR, the most well characterized interaction being DNA-binding domain- mediated dimerization, which is essential for the AR to bind DNA and regulate transcription. Additional AR interactions with potential to contribute to receptor dimerization include the intermolecular interaction between the AR amino terminal domain and ligand-binding domain known as the N-terminal/C-terminal interaction, and ligand-binding domain dimerization. In this review, we discuss each form of dimerization utilized by the AR to achieve transcriptional competence and highlight that dimerization through multiple domains is necessary for optimal AR signaling.Margaret M. Centenera, Jonathan M. Harris, Wayne D. Tilley and Lisa M. Butle
Androgenic regulation of lipid elongation in prostate cancer
No full textAbstractZeyad D Nassar, Margaret M Centenera, Jelle Machiels, Samuel J Polacek, Katarzyna Bloch, Wayne D Tilley, Luke A Selth, Lisa M Butler, and Johannes V Swinne
New Opportunities for Targeting the Androgen Receptor in Prostate Cancer
No full textRecent genomic analyses of metastatic prostate cancer have provided important insight into adaptive changes in androgen receptor (AR) signaling that underpin resistance to androgen deprivation therapies. Novel strategies are required to circumvent these AR-mediated resistance mechanisms and thereby improve prostate cancer survival. In this review, we present a summary of AR structure and function and discuss mechanisms of AR-mediated therapy resistance that represent important areas of focus for the development of new therapies.Margaret M. Centenera, Luke A. Selth, Esmaeil Ebrahimie, Lisa M. Butler and Wayne D. Tille
Androgen control of lipid metabolism in prostate cancer: novel insights and future applications
No full textOne of the most typical hallmarks of prostate cancer cells is their exquisite dependence on androgens, which is the basis of the widely applied androgen deprivation therapy. Among the variety of key cellular processes and functions that are regulated by androgens, lipid metabolism stands out by its complex regulation and its many intricate links with cancer cell biology. Here, we review our current knowledge on the links between androgens and lipid metabolism in prostate cancer, and highlight recent developments and insights into the links between key oncogenic stimuli and altered lipid synthesis and/or uptake that may hold significant potential for biomarker development and provide new vulnerabilities for therapeutic intervention.Lisa M Butler, Margaret M Centenera, Johannes V Swinne
The combination of metformin and valproic acid induces synergistic apoptosis in the presence of p53 and androgen signaling in prostate cancer
No full textAbstract not availableLinh N.K. Tran, Ganessan Kichenadasse, Lisa M. Butler, Margaret M. Centenera, Katherine L. Morel, Rebecca J. Ormsby, Michael Z. Michael, Karen M. Lower, and Pamela J. Syke
Heteroglosia y tradiciones discursivas: formas burlescas en la épica de M. del Barco Centenera
No full textEste artículo tiene como objetivo principal estudiar las formas burlescas en el poema épico Argentina y conquista del Río de la Plata, de Martín del Barco Centenera. En primer lugar, se abordará el concepto «tradiciones discursivas» que permitirá un encuadre más amplio del texto. Luego, se comentará la presencia de la heteroglosia en la construcción del poema, la que se ejemplificará en el uso de anécdotas y de tres recursos humorísticos: la ironía dramática y la sátira, vinculadas con cierta retórica del infortunio, y el grotesco. Estas características se unen al estilo didáctico presente en el poema, todo lo cual produce un texto que aporta innovaciones a la propia tradición
A novel combinatorial approach using androgen receptor-targeted agents for treatment of prostate cancer
No full textAbstract not availableLisa Butler, Margaret Centenera, Deborah Marrocco, Sarah Carter, Tina Bianco-Miotto and Wayne Tille
Hsp90: still a viable target in prostate cancer
No full textHeat shock protein 90 (Hsp90) is a molecular chaperone that regulates the maturation, activation and stability of critical signaling proteins that drive the development and progression of prostate cancer, including the androgen receptor. Despite robust preclinical data demonstrating anti-tumor activity of first-generation Hsp90 inhibitors in prostate cancer, poor clinical responses initially cast doubt over the clinical utility of this class of agent. Recent advances in compound design and development, use of novel preclinical models and further biological insights into Hsp90 structure and function have now stimulated a resurgence in enthusiasm for these drugs as a therapeutic option. This review highlights how the development of new-generation Hsp90 inhibitors with improved physical and pharmacological properties is unfolding, and discusses the potential contexts for their use either as single agents or in combination, for men with metastatic prostate cancer.Margaret M. Centenera, Alyssa K. Fitzpatrick, Wayne D. Tilley, Lisa M. Butle
Lipid elongation in prostate cancer is androgen regulated and a potential therapeutic target
No full textAs published in: Special Issue: Abstracts of the 19th Asia‐Pacific Prostate Cancer Conference 2018, 22 ‐ 25 August 2018, Brisbane, AustraliaZeyad D. Nassar, Margaret M. Centenera, Jelle Machiels, Irene Zinonos, Adrienne Hanson, Katarzyna Bloch, Natalie K. Ryan, Elizabeth D. Williams, Andreas Evdokiou, Wayne D. Tilley, Luke A. Selth, Lisa M. Butler and Johannes V. Swinne
Maximizing the therapeutic potential of HSP90 inhibitors
No full textHSP90 is required for maintaining the stability and activity of a diverse group of client proteins, including protein kinases, transcription factors, and steroid hormone receptors involved in cell signaling, proliferation, survival, oncogenesis, and cancer progression. Inhibition of HSP90 alters the HSP90-client protein complex, leading to reduced activity, misfolding, ubiquitination, and, ultimately, proteasomal degradation of client proteins. HSP90 inhibitors have demonstrated significant antitumor activity in a wide variety of preclinical models, with evidence of selectivity for cancer versus normal cells. In the clinic, however, the efficacy of this class of therapeutic agents has been relatively limited to date, with promising responses mainly observed in breast and lung cancer, but no major activity seen in other tumor types. In addition, adverse events and some significant toxicities have been documented. Key to improving these clinical outcomes is a better understanding of the cellular consequences of inhibiting HSP90 that may underlie treatment response or resistance. This review considers the recent progress that has been made in the study of HSP90 and its inhibitors and highlights new opportunities to maximize their therapeutic potential.Lisa M. Butler, Roberta Ferraldeschi, Heather K. Armstrong, Margaret M. Centenera, and Paul Workma
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