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

Metastatic prostate cancer (PCa) is primarily an androgen-dependent disease, which is treated with androgen deprivation therapy (ADT). Tumors usually develop resistance (castration-resistant PCa [CRPC]), but remain androgen receptor (AR) dependent.

Numerous mechanisms for AR-dependent resistance have been identified including expression of constitutively active AR splice variants lacking the hormone-binding domain. Recent clinical studies show that expression of the best-characterized AR variant, AR-V7, correlates with resistance to ADT and poor outcome. Whether AR-V7 is simply a constitutively active substitute for AR or has novel gene targets that cause unique downstream changes is unresolved. Several studies have shown that AR activation alters cell metabolism. Using LNCaP cells with inducible expression of AR-V7 as a model system, we found that AR-V7 stimulated growth, migration, and glycolysis measured by ECAR (extracellular acidification rate) similar to AR. However, further analyses using metabolomics and metabolic flux assays revealed several differences. Whereas AR increased citrate levels, AR-V7 reduced citrate mirroring metabolic shifts observed in CRPC patients. Flux analyses indicate that the low citrate is a result of enhanced utilization rather than a failure to synthesize citrate. Moreover, flux assays suggested that compared to AR, AR-V7 exhibits increased dependence on glutaminolysis and reductive carboxylation to produce some of the TCA (tricarboxylic acid cycle) metabolites. These findings suggest that these unique actions represent potential therapeutic targets.

Oncotarget. 2015 Sep 10 [Epub ahead of print]

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

Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. , Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. , Verna and Marrs McLean Department of Biochemistry, Baylor College of Medicine, Houston, TX, USA. , Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX, USA. , Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. , Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. , Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. , Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX, USA. , Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. , Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. , Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.

PubMed