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Androgens induce a distinct response of epithelial-mesenchymal transition factors in human prostate cancer cells

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Abstract

Inhibition of the androgen receptor (AR) is a major target of prostate cancer (PCa) therapy. However, prolonged androgen deprivation results eventually in castration-resistant PCa (CRPC) with metastasis and poor survival. Emerging evidence suggests that epithelial-mesenchymal transition (EMT) may facilitate castration-resistance and cancer metastasis in PCa. The human androgen-dependent, castration-sensitive prostate cancer (CSPC) cell line LNCaP and the CRPC cell line C4-2 are often used as a model system for human PCa. However, the role of the AR and the effect of AR antagonist (antiandrogen) treatment on the RNA expression of key factors of EMT including the long non-coding RNAs (lncRNAs) DRAIC in PCa cells remain elusive. Although as expected the established AR target genes PSA and FKBP5 are strongly induced by androgens in both cell lines, both E-cadherin and vimentin mRNA levels are upregulated by androgens in LNCaP but not in C4-2 cells by short- and long-term treatments. The mRNA levels of E-cadherin and vimentin remain unchanged by antiandrogen treatment in both cell lines. The expression of transcription factors that regulate EMT including Slug, Snail and ZEB1 and the lncRNA DRAIC were affected by androgen treatment in both cell lines. The mRNA level of Slug is upregulated by androgens and interestingly downregulated by antiandrogens in both cell lines. On the other hand, ZEB1 mRNA levels are strongly upregulated by androgens but remain unchanged by antiandrogens. In contrast, Snail mRNA levels are repressed by androgen treatment similar to DRAIC RNA levels. However, while antiandrogen treatment seems not to change Snail mRNA levels, antiandrogen treatments induce DRAIC RNA levels. Moreover, despite the strong upregulation of Zeb1 mRNA, no significant increase of the ZEB1 protein was observed indicating that despite androgen upregulation, posttranscriptional regulation of EMT controlling transcription factors occurs. SLUG protein was enhanced in both cell lines by androgens and reduced by antiandrogens. Taken together, our data suggest that the ligand-activated AR regulates the expression of several EMT key factors and antiandrogens counteract AR activity only on selected genes.

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Abbreviations

AA:

atraric acid

ADT:

androgen deprivation therapy

AR:

androgen receptor

Cas:

casodex, bicalutamide

CRPC:

castration-resistant prostate cancer

CSPC:

castration-sensitive prostate cancer

DHT:

dihydrotestosterone

EMT:

epithelial-mesenchymal transition

FKBP5:

FK506 binding protein 5

lncRNA:

long non-coding RNA

PCa:

prostate cancer

PSA:

prostate-specific antigen

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Acknowledgments

We are grateful to Gabriele Riesener for technical assistance and Mohsen Esmaeili for critical reading the manuscript. This work was supported by Jena University Hospital.

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Author notes

  1. Juliane Colditz

    Present address: Division of Endocrinology and Metabolic Bone Diseases, Department of Medicine III, Technical University Dresden, Dresden, Germany

  2. Benjamin Rupf

    Present address: Experimental Nephrology, Jena University Hospital, Jena, Germany

Authors and Affiliations

  1. Institute of Human Genetics, Jena University Hospital, Kollegiengasse 10, 07740, Jena, Germany

    Juliane Colditz, Benjamin Rupf, Caroline Maiwald & Aria Baniahmad

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  1. Juliane Colditz
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  2. Benjamin Rupf
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  3. Caroline Maiwald
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Correspondence to Aria Baniahmad.

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Colditz, J., Rupf, B., Maiwald, C. et al. Androgens induce a distinct response of epithelial-mesenchymal transition factors in human prostate cancer cells. Mol Cell Biochem 421, 139–147 (2016). https://doi.org/10.1007/s11010-016-2794-y

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  • DOI: https://doi.org/10.1007/s11010-016-2794-y

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