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Androgen induces expression of the multidrug resistance protein gene MRP4 in prostate cancer cells

C Cai1, J Omwancha, C-L Hsieh

  • 1Department of Biological Sciences, University of Toledo, Toledo, OH 43606, USA.

Prostate Cancer and Prostatic Diseases
|September 28, 2006
PubMed

Insights

Multidrug resistance-associated proteins (MRPs) like MRP4 may drive tumor resistance. Androgen receptor (AR) induction of MRP4 in prostate cancer cells increases resistance to certain chemotherapy drugs.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Multidrug resistance-associated proteins (MRPs) are implicated in tumor cell drug resistance.
  • The role of specific MRPs, such as MRP4, in prostate cancer (PC) progression and treatment resistance is not fully understood.

Purpose of the Study:

  • To investigate the role of MRP4 as an androgen receptor (AR)-regulated gene in prostate cancer.
  • To determine if MRP4 mediates resistance to chemotherapy in prostate cancer cells.

Main Methods:

  • Gene array analysis to identify AR-regulated genes.
  • Dihydrotestosterone (DHT) treatment of LNCaP, PC-3, and normal prostate epithelial cells to assess MRP4 expression.
  • Disruption of MRP4 expression in LNCaP cells using gene silencing techniques.
  • Assessment of LNCaP cell sensitivity to methotrexate and etoposide following MRP4 disruption.
  • Analysis of MRP4 expression in human prostate cancer tissues.

Main Results:

  • MRP4 was identified as an AR-regulated gene, with expression induced by DHT in LNCaP cells (both androgen-dependent and -independent).
  • Minimal MRP4 expression was observed in PC-3 cells and normal prostate epithelial cells.
  • Disruption of MRP4 expression sensitized LNCaP cells to methotrexate but not etoposide.
  • MRP4 expression was detected exclusively in metastatic prostate cancer tissues.

Conclusions:

  • Androgen receptor induction of MRP4 contributes to resistance against nucleotide-based chemotherapeutic drugs in prostate cancer cells.
  • MRP4 may serve as a therapeutic target for overcoming drug resistance in metastatic prostate cancer.

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