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Snail promotes resistance to enzalutamide through regulation of androgen receptor activity in prostate cancer.

Publication ,  Journal Article
Ware, KE; Somarelli, JA; Schaeffer, D; Li, J; Zhang, T; Park, S; Patierno, SR; Freedman, J; Foo, W-C; Garcia-Blanco, MA; Armstrong, AJ
Published in: Oncotarget
August 2, 2016

Treatment with androgen-targeted therapies can induce upregulation of epithelial plasticity pathways. Epithelial plasticity is known to be important for metastatic dissemination and therapeutic resistance. The goal of this study is to elucidate the functional consequence of induced epithelial plasticity on AR regulation during disease progression to identify factors important for treatment-resistant and metastatic prostate cancer. We pinpoint the epithelial plasticity transcription factor, Snail, at the nexus of enzalutamide resistance and prostate cancer metastasis both in preclinical models of prostate cancer and in patients. In patients, Snail expression is associated with Gleason 9-10 high-risk disease and is strongly overexpressed in metastases as compared to localized prostate cancer. Snail expression is also elevated in enzalutamide-resistant prostate cancer cells compared to enzalutamide-sensitive cells, and downregulation of Snail re-sensitizes enzalutamide-resistant cells to enzalutamide. While activation of Snail increases migration and invasion, it is also capable of promoting enzalutamide resistance in enzalutamide-sensitive cells. This Snail-mediated enzalutamide resistance is a consequence of increased full-length AR and AR-V7 expression and nuclear localization. Downregulation of either full-length AR or AR-V7 re-sensitizes cells to enzalutamide in the presence of Snail, thus connecting Snail-induced enzalutamide resistance directly to AR biology. Finally, we demonstrate that Snail is capable of mediating-resistance through AR even in the absence of AR-V7. These findings imply that increased Snail expression during progression to metastatic disease may prime cells for resistance to AR-targeted therapies by promoting AR activity in prostate cancer.

Duke Scholars

Published In

Oncotarget

DOI

EISSN

1949-2553

Publication Date

August 2, 2016

Volume

7

Issue

31

Start / End Page

50507 / 50521

Location

United States

Related Subject Headings

  • Transcription Factors
  • Tissue Array Analysis
  • Snail Family Transcription Factors
  • Prostatic Neoplasms
  • Phenylthiohydantoin
  • Nitriles
  • Neoplasm Metastasis
  • Neoplasm Invasiveness
  • Male
  • Humans
 

Citation

APA
Chicago
ICMJE
MLA
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Ware, K. E., Somarelli, J. A., Schaeffer, D., Li, J., Zhang, T., Park, S., … Armstrong, A. J. (2016). Snail promotes resistance to enzalutamide through regulation of androgen receptor activity in prostate cancer. Oncotarget, 7(31), 50507–50521. https://doi.org/10.18632/oncotarget.10476
Ware, Kathryn E., Jason A. Somarelli, Daneen Schaeffer, Jing Li, Tian Zhang, Sally Park, Steven R. Patierno, et al. “Snail promotes resistance to enzalutamide through regulation of androgen receptor activity in prostate cancer.Oncotarget 7, no. 31 (August 2, 2016): 50507–21. https://doi.org/10.18632/oncotarget.10476.
Ware KE, Somarelli JA, Schaeffer D, Li J, Zhang T, Park S, et al. Snail promotes resistance to enzalutamide through regulation of androgen receptor activity in prostate cancer. Oncotarget. 2016 Aug 2;7(31):50507–21.
Ware, Kathryn E., et al. “Snail promotes resistance to enzalutamide through regulation of androgen receptor activity in prostate cancer.Oncotarget, vol. 7, no. 31, Aug. 2016, pp. 50507–21. Pubmed, doi:10.18632/oncotarget.10476.
Ware KE, Somarelli JA, Schaeffer D, Li J, Zhang T, Park S, Patierno SR, Freedman J, Foo W-C, Garcia-Blanco MA, Armstrong AJ. Snail promotes resistance to enzalutamide through regulation of androgen receptor activity in prostate cancer. Oncotarget. 2016 Aug 2;7(31):50507–50521.

Published In

Oncotarget

DOI

EISSN

1949-2553

Publication Date

August 2, 2016

Volume

7

Issue

31

Start / End Page

50507 / 50521

Location

United States

Related Subject Headings

  • Transcription Factors
  • Tissue Array Analysis
  • Snail Family Transcription Factors
  • Prostatic Neoplasms
  • Phenylthiohydantoin
  • Nitriles
  • Neoplasm Metastasis
  • Neoplasm Invasiveness
  • Male
  • Humans