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

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.

SUBMITTER: Jurmeister S

PROVIDER: S-EPMC4116520 | biostudies-other | 2014 Jun

REPOSITORIES: biostudies-other

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

Jurmeister Sarah S Ramos-Montoya Antonio A Neal David E DE Fryer Lee G D LG

Oncotarget 20140601 11

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, w ...[more]

PMID: 25003216

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Project description:PURPOSE:The heterogeneity of androgen receptor (AR)-activity (AR-A) is well-characterized in heavily treated metastatic castration-resistant prostate cancer (mCRPC). However, the diversity and clinical implications of AR-A in treatment-naïve primary prostate cancer is largely unknown. We sought to characterize AR-A in localized prostate cancer and understand its molecular and clinical implications. EXPERIMENTAL DESIGN:Genome-wide expression profiles from prostatectomy or biopsy samples from 19,470 patients were used, all with independent pathology review. This was comprised of prospective discovery (n = 5,239) and validation (n = 12,728) cohorts, six retrospective institutional cohorts with long-term clinical outcomes data (n = 1,170), and The Cancer Genome Atlas (n = 333). RESULTS:A low AR-active subclass was identified, which comprised 9%-11% of each cohort, and was characterized by increased immune signaling, neuroendocrine expression, and decreased DNA repair. These tumors were predominantly ERG and basal subtype. Low AR-active tumors had significantly more rapid development of recurrence or metastatic disease across cohorts, which was maintained on multivariable analysis [HR, 2.61; 95% confidence interval (CI), 1.22-5.60; P = 0.014]. Low AR-active tumors were predicted to be more sensitive to PARP inhibition, platinum chemotherapy, and radiotherapy, and less sensitive to docetaxel and androgen-deprivation therapy. This was validated clinically, in that low AR-active tumors were less sensitive to androgen-deprivation therapy (OR, 0.41; 95% CI, 0.21-0.80; P = 0.008). CONCLUSIONS:Leveraging large-scale transcriptomic data allowed the identification of an aggressive subtype of treatment-naïve primary prostate cancer that harbors molecular features more analogous to mCRPC. This suggests that a preexisting subgroup of patients may have tumors that are predisposed to fail multiple current standard-of-care therapies and warrant dedicated therapeutic investigation.

Dataset Information

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

Publications

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

Similar Datasets

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