P-glycoprotein increases the efflux of the androgen dihydrotestosterone and reduces androgen responsive gene activity in prostate tumor cells

Prostate. 2004 Apr 1;59(1):77-90. doi: 10.1002/pros.10354.

Abstract

Background: P-glycoprotein (P-gp) is commonly associated with multi-drug resistance (MDR) in cancer cells and the efflux of a broad spectrum of chemicals from the cell, including many chemotherapeutics and certain steroid hormones. The impact of P-gp and mechanisms involved in androgen transport and cellular accumulation within normal and malignant prostate cells remains unclear.

Methods: Following incubation of LNCaP, PC-3, HeLa, and HeLa FLAG-androgen receptor (AR) cells with (3)H-dihydrotestosterone (DHT) alone and in combination with P-gp inhibitors, PSC-833 and verapamil, we examined the cellular accumulation and efflux of androgens, as well as gene transcriptional response.

Results: Our data reveal that the cellular transport and accumulation of DHT is dependent on the expression of functional AR and modulated by P-gp. P-gp over-expression by both transient transfection and aspirin treatment in LNCaP cells showed decreased intracellular DHT accumulation, further suggesting DHT efflux is P-gp regulated.

Conclusions: Androgen responsiveness may be modulated by P-gp in prostate cancer cells. The biological consequences of increased P-gp expression are decreased androgen accumulation and a corresponding decrease in androgen-regulated transcriptional activity and PSA gene expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Aspirin / pharmacology
  • Biological Transport
  • Blotting, Northern
  • Blotting, Western
  • Cyclosporins / pharmacology
  • Dihydrotestosterone / metabolism*
  • Female
  • Flow Cytometry
  • Gene Expression Regulation, Neoplastic / physiology*
  • HeLa Cells
  • Humans
  • Male
  • Neoplasms, Hormone-Dependent / genetics
  • Neoplasms, Hormone-Dependent / metabolism*
  • Precipitin Tests
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism*
  • RNA, Neoplasm / chemistry
  • RNA, Neoplasm / genetics
  • Receptors, Androgen / biosynthesis
  • Receptors, Androgen / metabolism*
  • Verapamil / pharmacology

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Anti-Inflammatory Agents, Non-Steroidal
  • Cyclosporins
  • RNA, Neoplasm
  • Receptors, Androgen
  • Dihydrotestosterone
  • Verapamil
  • valspodar
  • Aspirin