Browsing by Subject "Receptors, Androgen"

Now showing 1 - 7 of 7
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    Copper signaling axis as a target for prostate cancer therapeutics.
    (Cancer Res, 2014-10-15) Safi, R; Nelson, ER; Chitneni, SK; Franz, KJ; George, DJ; Zalutsky, MR; McDonnell, DP
    Previously published reports indicate that serum copper levels are elevated in patients with prostate cancer and that increased copper uptake can be used as a means to image prostate tumors. It is unclear, however, to what extent copper is required for prostate cancer cell function as we observed only modest effects of chelation strategies on the growth of these cells in vitro. With the goal of exploiting prostate cancer cell proclivity for copper uptake, we developed a "conditional lethal" screen to identify compounds whose cytotoxic actions were manifested in a copper-dependent manner. Emerging from this screen was a series of dithiocarbamates, which, when complexed with copper, induced reactive oxygen species-dependent apoptosis of malignant, but not normal, prostate cells. One of the dithiocarbamates identified, disulfiram (DSF), is an FDA-approved drug that has previously yielded disappointing results in clinical trials in patients with recurrent prostate cancer. Similarly, in our studies, DSF alone had a minimal effect on the growth of prostate cancer tumors when propagated as xenografts. However, when DSF was coadministered with copper, a very dramatic inhibition of tumor growth in models of hormone-sensitive and of castrate-resistant disease was observed. Furthermore, we determined that prostate cancer cells express high levels of CTR1, the primary copper transporter, and additional chaperones that are required to maintain intracellular copper homeostasis. The expression levels of most of these proteins are increased further upon treatment of androgen receptor (AR)-positive prostate cancer cell lines with androgens. Not surprisingly, robust CTR1-dependent uptake of copper into prostate cancer cells was observed, an activity that was accentuated by activation of AR. Given these data linking AR to intracellular copper uptake, we believe that dithiocarbamate/copper complexes are likely to be effective for the treatment of patients with prostate cancer whose disease is resistant to classical androgen ablation therapies.
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    Evaluating testosterone as a phenotypic integrator: From tissues to individuals to species.
    (Molecular and cellular endocrinology, 2019-10) Lipshutz, SE; George, EM; Bentz, AB; Rosvall, KA
    Hormones have the potential to bring about rapid phenotypic change; however, they are highly conserved over millions of years of evolution. Here, we examine the evolution of hormone-mediated phenotypes, and the extent to which regulation is achieved via independence or integration of the many components of endocrine systems. We focus on the sex steroid testosterone (T), its cognate receptor (androgen receptor) and related endocrine components. We pose predictions about the mechanisms underlying phenotypic integration, including coordinated sensitivity to T within and among tissues and along the HPG axis. We then assess these predictions with case studies from wild birds, asking whether gene expression related to androgenic signaling naturally co-varies among individuals in ways that would promote phenotypic integration. Finally, we review how mechanisms of integration and independence vary over developmental or evolutionary time, and we find limited support for integration.
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    Molecular determinants for enzalutamide-induced transcription in prostate cancer.
    (Nucleic acids research, 2019-11) Yuan, Fuwen; Hankey, William; Wu, Dayong; Wang, Hongyan; Somarelli, Jason; Armstrong, Andrew J; Huang, Jiaoti; Chen, Zhong; Wang, Qianben
    Enzalutamide, a second-generation androgen receptor (AR) antagonist, has demonstrated clinical benefit in men with prostate cancer. However, it only provides a temporary response and modest increase in survival, indicating a rapid evolution of resistance. Previous studies suggest that enzalutamide may function as a partial transcriptional agonist, but the underlying mechanisms for enzalutamide-induced transcription remain poorly understood. Here, we show that enzalutamide stimulates expression of a novel subset of genes distinct from androgen-responsive genes. Treatment of prostate cancer cells with enzalutamide enhances recruitment of pioneer factor GATA2, AR, Mediator subunits MED1 and MED14, and RNA Pol II to regulatory elements of enzalutamide-responsive genes. Mechanistically, GATA2 globally directs enzalutamide-induced transcription by facilitating AR, Mediator and Pol II loading to enzalutamide-responsive gene loci. Importantly, the GATA2 inhibitor K7174 inhibits enzalutamide-induced transcription by decreasing binding of the GATA2/AR/Mediator/Pol II transcriptional complex, contributing to sensitization of prostate cancer cells to enzalutamide treatment. Our findings provide mechanistic insight into the future combination of GATA2 inhibitors and enzalutamide for improved AR-targeted therapy.
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    Ornithine Decarboxylase Is Sufficient for Prostate Tumorigenesis via Androgen Receptor Signaling.
    (The American journal of pathology, 2016-12) Shukla-Dave, Amita; Castillo-Martin, Mireia; Chen, Ming; Lobo, Jose; Gladoun, Nataliya; Collazo-Lorduy, Ana; Khan, Faisal M; Ponomarev, Vladimir; Yi, Zhengzi; Zhang, Weijia; Pandolfi, Pier P; Hricak, Hedvig; Cordon-Cardo, Carlos
    Increased polyamine synthesis is known to play an important role in prostate cancer. We aimed to explore its functional significance in prostate tumor initiation and its link to androgen receptor (AR) signaling. For this purpose, we generated a new cell line derived from normal epithelial prostate cells (RWPE-1) with overexpression of ornithine decarboxylase (ODC) and used it for in vitro and in vivo experiments. We then comprehensively analyzed the expression of the main metabolic enzymes of the polyamine pathway and spermine abundance in 120 well-characterized cases of human prostate cancer and high-grade prostate intraepithelial neoplasia (HGPIN). Herein, we show that the ODC-overexpressing prostate cells underwent malignant transformation, revealing that ODC is sufficient for de novo tumor initiation in 94% of injected mice. This oncogenic capacity was acquired through alteration of critical signaling networks, including AR, EIF2, and mTOR/MAPK. RNA silencing experiments revealed the link between AR signaling and polyamine metabolism. Human prostate cancers consistently demonstrated up-regulation of the main polyamine enzymes analyzed (ODC, polyamine oxidase, and spermine synthase) and reduction of spermine. This phenotype was also dominant in HGPIN, rendering it a new biomarker of malignant transformation. In summary, we report that ODC plays a key role in prostate tumorigenesis and that the polyamine pathway is altered as early as HGPIN.
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    Preclinical and Coclinical Studies in Prostate Cancer.
    (Cold Spring Harbor perspectives in medicine, 2018-04-02) Chen, Ming; Pandolfi, Pier Paolo
    Men who develop metastatic castration-resistant prostate cancer (mCRPC) will invariably succumb to their disease. Thus there remains a pressing need for preclinical testing of new drugs and drug combinations for late-stage prostate cancer (PCa). Insights from the mCRPC genomic landscape have revealed that, in addition to sustained androgen receptor (AR) signaling, there are other actionable molecular alterations and distinct molecular subclasses of PCa; however, the rate at which this knowledge translates into patient care via current preclinical testing is painfully slow and inefficient. Here, we will highlight the issues involved and discuss a new translational platform, "the co-clinical trial project," to expedite current preclinical studies and optimize clinical trial and experimental drug testing. With this platform, in vivo preclinical and early clinical studies are closely aligned, enabling in vivo testing of drugs using genetically engineered mouse models (GEMMs) in defined genetic contexts to personalize individual therapies. We will discuss the principles and essential components of this novel paradigm, representative success stories and future therapeutic options for mCRPC that should be explored.
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    Proteome-wide muscle protein fractional synthesis rates predict muscle mass gain in response to a selective androgen receptor modulator in rats.
    (Am J Physiol Endocrinol Metab, 2016-03-15) Shankaran, Mahalakshmi; Shearer, Todd W; Stimpson, Stephen A; Turner, Scott M; King, Chelsea; Wong, Po-Yin Anne; Shen, Ying; Turnbull, Philip S; Kramer, Fritz; Clifton, Lisa; Russell, Alan; Hellerstein, Marc K; Evans, William J
    Biomarkers of muscle protein synthesis rate could provide early data demonstrating anabolic efficacy for treating muscle-wasting conditions. Androgenic therapies have been shown to increase muscle mass primarily by increasing the rate of muscle protein synthesis. We hypothesized that the synthesis rate of large numbers of individual muscle proteins could serve as early response biomarkers and potentially treatment-specific signaling for predicting the effect of anabolic treatments on muscle mass. Utilizing selective androgen receptor modulator (SARM) treatment in the ovariectomized (OVX) rat, we applied an unbiased, dynamic proteomics approach to measure the fractional synthesis rates (FSR) of 167-201 individual skeletal muscle proteins in triceps, EDL, and soleus. OVX rats treated with a SARM molecule (GSK212A at 0.1, 0.3, or 1 mg/kg) for 10 or 28 days showed significant, dose-related increases in body weight, lean body mass, and individual triceps but not EDL or soleus weights. Thirty-four out of the 94 proteins measured from the triceps of all rats exhibited a significant, dose-related increase in FSR after 10 days of SARM treatment. For several cytoplasmic proteins, including carbonic anhydrase 3, creatine kinase M-type (CK-M), pyruvate kinase, and aldolase-A, a change in 10-day FSR was strongly correlated (r(2) = 0.90-0.99) to the 28-day change in lean body mass and triceps weight gains, suggesting a noninvasive measurement of SARM effects. In summary, FSR of multiple muscle proteins measured by dynamics of moderate- to high-abundance proteins provides early biomarkers of the anabolic response of skeletal muscle to SARM.
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    Reduced prostate branching morphogenesis in stromal fibroblast, but not in epithelial, estrogen receptor α knockout mice.
    (Asian journal of andrology, 2012-07) Chen, Ming; Yeh, Chiuan-Ren; Shyr, Chih-Rong; Lin, Hsiu-Hsia; Da, Jun; Yeh, Shuyuan
    Early studies suggested that estrogen receptor alpha (ERα) is involved in estrogen-mediated imprinting effects in prostate development. We recently reported a more complete ERα knockout (KO) mouse model via mating β-actin Cre transgenic mice with floxed ERα mice. These ACTB-ERαKO male mice showed defects in prostatic branching morphogenesis, which demonstrates that ERα is necessary to maintain proliferative events in the prostate. However, within which prostate cell type ERα exerts those important functions remains to be elucidated. To address this, we have bred floxed ERα mice with either fibroblast-specific protein (FSP)-Cre or probasin-Cre transgenic mice to generate a mouse model that has deleted ERα gene in either stromal fibroblast (FSP-ERαKO) or epithelial (pes-ERαKO) prostate cells. We found that circulating testosterone and fertility were not altered in FSP-ERαKO and pes-ERαKO male mice. Prostates of FSP-ERαKO mice have less branching morphogenesis compared to that of wild-type littermates. Further analyses indicated that loss of stromal ERα leads to increased stromal apoptosis, reduced expression of insulin-like growth factor-1 (IGF-1) and FGF10, and increased expression of BMP4. Collectively, we have established the first in vivo prostate stromal and epithelial selective ERαKO mouse models and the results from these mice indicated that stromal fibroblast ERα plays important roles in prostatic branching morphogenesis via a paracrine fashion. Selective deletion of the ERα gene in mouse prostate epithelial cells by probasin-Cre does not affect the regular prostate development and homeostasis.