Differential regulation of metabolic pathways by androgen receptor (AR) and its constitutively active splice variant, AR-V7, in prostate cancer cells

• DOI: 10.18632/oncotarget.5585
• Publication Date: 2015-09-29T21:54:23Z
• Authors: Ayesha A. Shafi; Vasanta Putluri; James M. Arnold; Efrosini Tsouko; Suman Maity; Justin M. Roberts; Cristian Coarfa; Daniel E. Frigo; Nagireddy Putluri; Arun Sreekumar; Nancy L. Weigel
• Keywords: splice

// Ayesha A. Shafi 1 , Vasanta Putluri 1,2,3 James M. Arnold 2 Efrosini Tsouko 4 Suman Maity Justin Roberts Cristian Coarfa 1,3 Daniel E. Frigo 4,5 Nagireddy Arun Sreekumar and Nancy L. Weigel 1,6 Department of Molecular Cellular Biology, Baylor College Medicine, Houston, TX, USA Verna Marrs McLean Biochemistry, 3 Alkek Center for Discovery, Nuclear Receptors Cell Signaling, Biology University 5 Genomic Medicine Program, Houston Methodist Research Institute, 6 Scott Urology, Correspondence to: Weigel, email: Keywords : prostate cancer, androgen receptor, splice variant, metabolism, LNCaP Received July 14, 2015 Accepted August 19, Published September 10, Abstract Metastatic cancer (PCa) is primarily an androgen-dependent disease, which treated with deprivation therapy (ADT). Tumors usually develop resistance (castration-resistant PCa [CRPC]), but remain receptor (AR) dependent. Numerous mechanisms AR-dependent have been identified including expression constitutively active AR variants lacking the hormone-binding domain. Recent clinical studies show that best-characterized AR-V7, correlates to ADT poor outcome. Whether AR-V7 simply a substitute or has novel gene targets cause unique downstream changes unresolved. Several shown activation alters cell metabolism. Using cells inducible as model system, we found stimulated growth, migration, glycolysis measured by ECAR (extracellular acidification rate) similar AR. However, further analyses using metabolomics metabolic flux assays revealed several differences. Whereas increased citrate levels, reduced mirroring shifts observed in CRPC patients. Flux indicate low result enhanced utilization rather than failure synthesize citrate. Moreover, suggested compared AR, exhibits dependence on glutaminolysis reductive carboxylation produce some TCA (tricarboxylic acid cycle) metabolites. These findings suggest these actions represent potential therapeutic targets.