title: Endostatin inhibits androgen-independent prostate cancer growth by suppressing nuclear receptor-mediated oxidative stress.
abstract: Androgen-deprivation therapy has been identified to induce oxidative stress in prostate cancer (PCa), leading to reactivation of androgen receptor (AR) signaling in a hormone-refractory manner. Thus, antioxidant therapies have gained attention as adjuvants for castration-resistant PCa. Here, we report for the first time that human endostatin (ES) prevents androgen-independent growth phenotype in PCa cells through its molecular targeting of AR and glucocorticoid receptor (GR) and downstream pro-oxidant signaling. This reversal after ES treatment significantly decreased PCa cell proliferation through down-regulation of GR and up-regulation of manganese superoxide dismutase and reduced glutathione levels. Proteome and biochemical analyses of ES-treated PCa cells further indicated a significant up-regulation of enzymes in the major reactive oxygen species (ROS) scavenging machinery, including catalase, glutathione synthetase, glutathione reductase, NADPH-cytochrome P450 reductase, biliverdin reductase, and thioredoxin reductase, resulting in a concomitant reduction of intracellular ROS. ES further augmented the antioxidant system through up-regulation of glucose influx, the pentose phosphate pathway, and NAD salvaging pathways. This shift in cancer cell redox homeostasis by ES significantly decreased the effect of protumorigenic oxidative machinery on androgen-independent PCa growth, suggesting that ES can suppress GR-induced resistant phenotype upon AR antagonism and that the dual targeting action of ES on AR and GR can be further translated to PCa therapy.-Lee, J. H., Kang, M., Wang, H., Naik, G., Mobley, J. A., Sonpavde, G., Garvey, W. T., Darley-Usmar, V. M., Ponnazhagan, S. Endostatin inhibits androgen-independent prostate cancer growth by suppressing nuclear receptor-mediated oxidative stress.
authors.affiliation: Department of Pathology, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Joo Hyoung
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Nutrition Sciences, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Minsung
authors.initials: M
authors.lastname: Kang
authors.affiliation: Department of Pathology, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: University of Alabama at Birmingham (UAB) Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Gurudatta
authors.initials: G
authors.lastname: Naik
authors.affiliation: Department of Surgery, The University of Alabama at Birmingham, Birmingham, Alabama, USA; and.
authors.forename: James A
authors.initials: JA
authors.lastname: Mobley
authors.affiliation: University of Alabama at Birmingham (UAB) Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Guru
authors.initials: G
authors.lastname: Sonpavde
authors.affiliation: Department of Nutrition Sciences, The University of Alabama at Birmingham, Birmingham, Alabama, USA.|Birmingham Veterans Affairs Medical Center, Birmingham, Alabama, USA.
authors.forename: W Timothy
authors.initials: WT
authors.lastname: Garvey
authors.affiliation: Department of Pathology, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Victor M
authors.initials: VM
authors.lastname: Darley-Usmar
authors.affiliation: Department of Pathology, The University of Alabama at Birmingham, Birmingham, Alabama, USA; pons@uab.edu.
authors.forename: Selvarangan
authors.initials: S
authors.lastname: Ponnazhagan
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D015536:Down-Regulation; D043169:Endostatins / Q000494:pharmacology*; D005980:Glutathione Reductase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D009251:NADPH-Ferrihemoprotein Reductase / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D013880:Thioredoxin-Disulfide Reductase / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D043169:Endostatins; D011944:Receptors, Androgen; D011965:Receptors, Glucocorticoid; D002374:Catalase; D013482:Superoxide Dismutase; D009251:NADPH-Ferrihemoprotein Reductase; D005980:Glutathione Reductase; D013880:Thioredoxin-Disulfide Reductase
keywords: androgen receptor; androgen-deprivation therapy; castration resistance; glucocorticoid receptor; reactive oxygen species