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

Ayesha A. Shafi, Vasanta Putluri, James M. Arnold, Efrosini Tsouko, Suman Maity, Justin M. Roberts, Cristian Coarfa, Daniel Frigo, Nagireddy Putluri, Arun Sreekumar, Nancy L. Weigel

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

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 hormonebinding domain. Recent clinical studies show that expression of the best-characterized AR variant, AR-V7, correlates with resistance to ADT and poor outcome. Whether ARV7 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.

Original languageEnglish (US)
Pages (from-to)31997-32012
Number of pages16
JournalOncotarget
Volume6
Issue number31
DOIs
StatePublished - 2015

Keywords

  • Androgen receptor
  • LNCaP
  • Metabolism
  • Prostate cancer
  • Splice variant

ASJC Scopus subject areas

  • Oncology

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