Oncotarget

Research Papers:

Transcriptomic analysis reveals inhibition of androgen receptor activity by AMPK in prostate cancer cells

Sarah Jurmeister, Antonio Ramos-Montoya, David E. Neal and Lee G.D. Fryer _

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Oncotarget. 2014; 5:3785-3799. https://doi.org/10.18632/oncotarget.1997

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Abstract

Sarah Jurmeister1, Antonio Ramos-Montoya1, David E. Neal1,2 and Lee G.D. Fryer1

1 Uro-Oncology Research Group, Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, UK

2 Dept of Urology, University of Cambridge, S4, Dept of Oncology, Addenbrooke’s Hospital, UK

Correspondence:

Lee Fryer, email:

Keywords: Androgen receptor, AMPK, prostate cancer, cancer metabolism, transcription

Received: March 24, 2014 Accepted: May 19, 2014 Published: May 21, 2014

Abstract

Metabolic alterations contribute to prostate cancer development and progression; however, the role of the central metabolic regulator AMP-activated protein kinase (AMPK) remains controversial. The androgen receptor (AR), a key driver of prostate cancer, regulates prostate cancer cell metabolism by driving the expression of a network of metabolic genes and activates AMPK through increasing the expression of one of its upstream kinases. To more clearly define the role of AMPK in prostate cancer, we performed expression profiling following pharmacologic activation of this kinase. We found that genes down-regulated upon AMPK activation were over-expressed in prostate cancer, consistent with a tumour suppressive function of AMPK. Strikingly, we identified the AR as one of the most significantly enriched transcription factors mediating gene expression changes downstream of AMPK signalling in prostate cancer cells. Activation of AMPK inhibited AR transcriptional activity and reduced androgen-dependent expression of known AR target genes. Conversely, knock-down of AMPK increased AR activity. Modulation of AR expression could not explain these effects. Instead, we observed that activation of AMPK reduced nuclear localisation of the AR. We thus propose the presence of a negative feedback loop in prostate cancer cells whereby AR activates AMPK and AMPK feeds back to limit AR-driven transcription.


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PII: 1997