Dataset Information

Metformin anti-tumor effect via disruption of the MID1 translational regulator complex and AR downregulation in prostate cancer cells.

ABSTRACT:

Background

Metformin is an approved drug prescribed for diabetes. Its role as an anti-cancer agent has drawn significant attention because of its minimal side effects and low cost. However, its mechanism of anti-tumour action has not yet been fully clarified.

Methods

The effect on cell growth was assessed by cell counting. Western blot was used for analysis of protein levels, Boyden chamber assays for analyses of cell migration and co-immunoprecipitation (CoIP) followed by western blot, PCR or qPCR for analysis of protein-protein and protein-mRNA interactions.

Results

Metformin showed an anti-proliferative effect on a wide range of prostate cancer cells. It disrupted the AR translational MID1 regulator complex leading to release of the associated AR mRNA and subsequently to downregulation of AR protein in AR positive cell lines. Inhibition of AR positive and negative prostate cancer cells by metformin suggests involvement of additional targets. The inhibitory effect of metformin was mimicked by disruption of the MID1-?4/PP2A protein complex by siRNA knockdown of MID1 or ?4 whereas AMPK activation was not required.

Conclusions

Findings reported herein uncover a mechanism for the anti-tumor activity of metformin in prostate cancer, which is independent of its anti-diabetic effects. These data provide a rationale for the use of metformin in the treatment of hormone naïve and castration-resistant prostate cancer and suggest AR is an important indirect target of metformin.

SUBMITTER: Demir U

PROVIDER: S-EPMC3929757 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Publications

Metformin anti-tumor effect via disruption of the MID1 translational regulator complex and AR downregulation in prostate cancer cells.

Demir Ummuhan U Koehler Andrea A Schneider Rainer R Schweiger Susann S Klocker Helmut H

BMC cancer 20140131

<h4>Background</h4>Metformin is an approved drug prescribed for diabetes. Its role as an anti-cancer agent has drawn significant attention because of its minimal side effects and low cost. However, its mechanism of anti-tumour action has not yet been fully clarified.<h4>Methods</h4>The effect on cell growth was assessed by cell counting. Western blot was used for analysis of protein levels, Boyden chamber assays for analyses of cell migration and co-immunoprecipitation (CoIP) followed by western ...[more]

PMID: 24484909

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Project description:Lineage plasticity in advanced prostate cancer (PCa) involves a corruption of differentiation programs, often regulated by the androgen receptor (AR). This study explores an under-explored cistromic mechanism: how type II nuclear receptors like RARγ may affect AR control of prodifferentiation transcriptional programs. The components of the RARγ complex are dynamic in PCa cell models and enriched for miR-96 targets, partly due to m6A-marked miR-96 recognition elements. Restoration of TACC1 and RARγ, both miR-96 repressed targets, in 22Rv1 cells augmented the AR cistrome, particularly in active enhancers and super-enhancers. In 22Rv1 cells the RARγ complex was enriched for bookmarking components, and created nucleosome-free chromatin enriched for H3K27ac, and profoundly enhanced the dihydrotestosterone (DHT)-dependent AR cistrome in G2/M cells and are all indicative of bookmarking functions. The RARγ-dependent and DHT-regulated AR cistrome-transcriptome relationships were significantly strengthened, notably in Active Enhancers, associated with AR-dependent luminal differentiation transcriptional programs. Interestingly RARγ-dependent AR cistromes significantly overlapped with ONECUT2, but the comparative transcriptional analyses supported an antagonistic function between RARγ and ONECUT2. Finally, the footprint of these data was detected in advanced tumors. For example, the miR-96 targetome and RARγ/ONECUT2 antagonized genes were significantly similar to AR signaling inhibitor-induced alternative lineages and metastatic tumors. Partial correlation analyses revealed RARγ CoAs identified by RIME, including SSRP1, significantly strengthened the correlations between AR and RARγ-TACC1-dependent DHT-regulated target genes in SU2C advanced PCa, and differentially-expressed genes between tumors with high RARγ and low ONECUT2 expression compared to the reverse was significantly associated with elevated AR score. In summary, the RARγ complex, selectively targeted by miR-96 functions as an enhancer re-programmer by bookmarking chromatin in G2/M cells to sustain and restrict AR transcriptional competency required for programs such as luminal differentiation, and antagonizing ONECUT2.

Project description:BackgroundAndrogen receptor (AR) splice variants (AR-Vs) have been discussed as a biomarker in prostate cancer (PC). However, some reports question the predictive property of AR-Vs. From a mechanistic perspective, the connection between AR full length (AR-FL) and AR-Vs is not fully understood. Here, we aimed to investigate the dependence of AR-FL and AR-V expression levels on AR gene activity. Additionally, we intended to comprehensively analyze presence of AR-FL and three clinically relevant AR-Vs (AR-V3, AR-V7 and AR-V9) in different stages of disease, especially with respect to clinical utility in PC patients undergoing AR targeted agent (ARTA) treatment.MethodsAR-FL and AR-V levels were analyzed in PC and non-PC cell lines upon artificial increase of AR pre-mRNA using either drug treatment or AR gene activation. Furthermore, expression of AR-FL and AR-Vs was determined in PC specimen at distinct stages of disease (primary (n = 10) and metastatic tissues (n = 20), liquid biopsy samples (n = 422), mCRPC liquid biopsy samples of n = 96 patients starting novel treatment). Finally, baseline AR-FL and AR-V status was correlated with clinical outcome in a defined cohort of n = 65 mCRPC patients undergoing ARTA treatment.ResultsWe revealed rising levels of AR-FL accompanied with appearance and increase of AR-Vs in dependence of elevated AR pre-mRNA levels. We also noticed increase in AR-FL and AR-V levels throughout disease progression. AR-V expression was always associated with high AR-FL levels without any sample being solely AR-V positive. In patients undergoing ARTA treatment, AR-FL did show prognostic, yet not predictive validity. Additionally, we observed a substantial clinical response to ARTA treatment even in AR-V positive patients. Accordingly, multivariate analysis did not demonstrate independent significance of AR-Vs in neither predictive nor prognostic clinical utility.ConclusionWe demonstrate a correlation between AR-FL and AR-V expression during PC progression; with AR-V expression being a side-effect of elevated AR pre-mRNA levels. Clinically, AR-V positivity relies on high levels of AR-FL, making cells still vulnerable to ARTA treatment, as demonstrated by AR-FL and AR-V positive patients responding to ARTA treatment. Thus, AR-FL and AR-V might be considered as a prognostic, yet not predictive biomarker in mCRPC patients.

Dataset Information

Metformin anti-tumor effect via disruption of the MID1 translational regulator complex and AR downregulation in prostate cancer cells.

Background

Methods

Results

Conclusions

Publications

Metformin anti-tumor effect via disruption of the MID1 translational regulator complex and AR downregulation in prostate cancer cells.

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