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      Upregulation of glucocorticoid receptor‐mediated glucose transporter 4 in enzalutamide‐resistant prostate cancer

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          Abstract

          Enzalutamide (Enz) is a second‐generation androgen receptor (AR) antagonist for castration‐resistant prostate cancer (CRPC) therapy, and it prolongs survival time in these patients. However, during Enz treatment, CRPC patients usually acquire resistance to Enz and often show cross‐resistance to other AR signaling inhibitors. Although glucocorticoid receptor (GR) is involved in this resistance, the role of GR has not yet been clarified. Here, we report that chronic Enz treatment induced GR‐mediated glucose transporter 4 (GLUT4) upregulation, and that upregulation was associated with resistance to Enz and other AR signaling inhibitors. Additionally, inhibition of GLUT4 suppressed cell proliferation in Enz‐resistant prostate cancer cells, which recovered from Enz resistance and cross‐resistance without changes in GR expression. Thus, a combination of Enz and a GLUT4 inhibitor could be useful in Enz‐resistant CRPC patients.

          Abstract

          Chronic enzalutamide (Enz) treatment induced glucocorticoid receptor (GR)‐mediated glucose transporter 4 (GLUT4) upregulation, and the upregulation was associated with resistance to Enz and other androgen receptor signaling inhibitors. Additionally, inhibition of GLUT4 suppressed cell proliferation in Enz‐resistant prostate cancer cells, which recovered from Enz resistance and cross‐resistance without changes in GR expression.

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          Most cited references 46

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          The Emerging Hallmarks of Cancer Metabolism.

          Tumorigenesis is dependent on the reprogramming of cellular metabolism as both direct and indirect consequence of oncogenic mutations. A common feature of cancer cell metabolism is the ability to acquire necessary nutrients from a frequently nutrient-poor environment and utilize these nutrients to both maintain viability and build new biomass. The alterations in intracellular and extracellular metabolites that can accompany cancer-associated metabolic reprogramming have profound effects on gene expression, cellular differentiation, and the tumor microenvironment. In this Perspective, we have organized known cancer-associated metabolic changes into six hallmarks: (1) deregulated uptake of glucose and amino acids, (2) use of opportunistic modes of nutrient acquisition, (3) use of glycolysis/TCA cycle intermediates for biosynthesis and NADPH production, (4) increased demand for nitrogen, (5) alterations in metabolite-driven gene regulation, and (6) metabolic interactions with the microenvironment. While few tumors display all six hallmarks, most display several. The specific hallmarks exhibited by an individual tumor may ultimately contribute to better tumor classification and aid in directing treatment.
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            Molecular determinants of resistance to antiandrogen therapy.

            Using microarray-based profiling of isogenic prostate cancer xenograft models, we found that a modest increase in androgen receptor mRNA was the only change consistently associated with the development of resistance to antiandrogen therapy. This increase in androgen receptor mRNA and protein was both necessary and sufficient to convert prostate cancer growth from a hormone-sensitive to a hormone-refractory stage, and was dependent on a functional ligand-binding domain. Androgen receptor antagonists showed agonistic activity in cells with increased androgen receptor levels; this antagonist-agonist conversion was associated with alterations in the recruitment of coactivators and corepressors to the promoters of androgen receptor target genes. Increased levels of androgen receptor confer resistance to antiandrogens by amplifying signal output from low levels of residual ligand, and by altering the normal response to antagonists. These findings provide insight toward the design of new antiandrogens.
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              FoxA1 specifies unique androgen and glucocorticoid receptor binding events in prostate cancer cells.

              The forkhead protein FoxA1 has functions other than a pioneer factor, in that its depletion brings about a significant redistribution in the androgen receptor (AR) and glucocorticoid receptor (GR) cistromes. In this study, we found a novel function for FoxA1 in defining the cell-type specificity of AR- and GR-binding events in a distinct fashion, namely, for AR in LNCaP-1F5 cells and for GR in VCaP cells. We also found different, cell-type and receptor-specific compilations of cis-elements enriched adjacent to the AR- and GR-binding sites. The AR pathway is central in prostate cancer biology, but the role of GR is poorly known. We find that AR and GR cistromes and transcription programs exhibit significant overlap, and GR regulates a large number of genes considered to be AR pathway-specific. This raises questions about the role of GR in maintaining the AR pathway under androgen-deprived conditions in castration-resistant prostate cancer patients. However, in the presence of androgen, ligand-occupied GR acts as a partial antiandrogen and attenuates the AR-dependent transcription program. . ©2012 AACR
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                Author and article information

                Contributors
                uro-hosi@fmu.ac.jp
                Journal
                Cancer Sci
                Cancer Sci
                10.1111/(ISSN)1349-7006
                CAS
                Cancer Science
                John Wiley and Sons Inc. (Hoboken )
                1347-9032
                1349-7006
                11 March 2021
                May 2021
                : 112
                : 5 ( doiID: 10.1111/cas.v112.5 )
                : 1899-1910
                Affiliations
                [ 1 ] Department of Urology Fukushima Medical University School of Medicine Fukushima Japan
                Author notes
                [* ] Correspondence

                Seiji Hoshi, Department of Urology, Fukushima Medical University School of Medicine, Fukushima, Japan.

                Email: uro-hosi@ 123456fmu.ac.jp

                Article
                CAS14865
                10.1111/cas.14865
                8088914
                33619826
                © 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                Page count
                Figures: 11, Tables: 0, Pages: 12, Words: 7168
                Product
                Categories
                Original Article
                Original Articles
                Cell, Molecular, and Stem Cell Biology
                Custom metadata
                2.0
                May 2021
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.0.2 mode:remove_FC converted:02.05.2021

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