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Differential gene expression induced by anti-cancer agent plumbagin is mediated by androgen receptor in prostate cancer cells

ABSTRACT: Plumbagin treatment of mice harboring PTEN-P2 tumors in the prostate or on prostate tissue maintained in vivo results in tumor regression when coupled with androgen deprivation therapy. This suggested that dihydrotestosterone (DHT) production in the testes prevents tumor regression due to plumbagin treatment by an unknown mechanism. We performed RNA-seq analysis on cells treated with plumbagin, DHT, or both, and analyzed differential gene expression using RNA-seq. DHT and plumbagin synergize to differentially regulate many genes that are not differentially regulated by either agent alone. For many genes, increases in mRNAs caused by DHT are sharply down-regulated by plumbagin, and some transcripts increase or decrease in response to plumbagin in a DHT-dependent manner. We also observed that plumbagin causes extensive RNA damage independently of DHT. We also include data from a simple time course experiment in which gene expression in response to DHT was studied using RNA-seq.

ORGANISM(S): Mus musculus

PROVIDER: GSE104305 | GEO | 2017/09/28

SECONDARY ACCESSION(S): PRJNA412309

REPOSITORIES: GEO

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Project description:This a model from the article: Mathematical model for the androgenic regulation of the prostate in intact and castrated adult male rats. Potter LK, Zager MG, Barton HA. Am J Physiol Endocrinol Metab. 2006:91(5):E952-64. 16757547 , Abstract: The testicular-hypothalamic-pituitary axis regulates male reproductive system functions. Understanding these regulatory mechanisms is important for assessing the reproductive effects of environmental and pharmaceutical androgenic and antiandrogenic compounds. A mathematical model for the dynamics of androgenic synthesis, transport, metabolism, and regulation of the adult rodent ventral prostate was developed on the basis of a model by Barton and Anderson (1997). The model describes the systemic and local kinetics of testosterone (T), 5alpha-dihydrotestosterone (DHT), and luteinizing hormone (LH), with metabolism of T to DHT by 5alpha-reductase in liver and prostate. Also included are feedback loops for the positive regulation of T synthesis by LH and negative regulation of LH by T and DHT. The model simulates maintenance of the prostate as a function of hormone concentrations and androgen receptor (AR)-mediated signal transduction. The regulatory processes involved in prostate size and function include cell proliferation, apoptosis, fluid production, and 5alpha-reductase activity. Each process is controlled through the occupancy of a representative gene by androgen-AR dimers. The model simulates prostate dynamics for intact, castrated, and intravenous T-injected rats. After calibration, the model accurately captures the castration-induced regression of the prostate compared with experimental data that show that the prostate regresses to approximately 17 and 5% of its intact weight at 14 and 30 days postcastration, respectively. The model also accurately predicts serum T and AR levels following castration compared with data. This model provides a framework for quantifying the kinetics and effects of environmental and pharmaceutical endocrine active compounds on the prostate. This model was taken from the CellML repository and automatically converted to SBML. The original model was: Potter, Zager, Barton (2006) - version03 The original CellML model was created by: Lloyd, Catherine, May c.lloyd@auckland.ac.nz The University of Auckland Auckland Bioengineering Institute This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information. In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not.. To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

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Differential gene expression induced by anti-cancer agent plumbagin is mediated by androgen receptor in prostate cancer cells

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