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P‐glycoprotein increases the efflux of the androgen dihydrotestosterone and reduces androgen responsive gene activity in prostate tumor cells
Author(s) -
Fedoruk Matthew N.,
GiménezBonafé Pepita,
Guns Emma S.,
Mayer Lawrence D.,
Nelson Colleen C.
Publication year - 2003
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.10354
Subject(s) - dihydrotestosterone , lncap , androgen , androgen receptor , endocrinology , efflux , medicine , prostate cancer , p glycoprotein , biology , cancer research , chemistry , hormone , cancer , biochemistry , multiple drug resistance , antibiotics
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. © 2004 Wiley‐Liss, Inc.