Studies on the human prostatic cancer cell line LNCaP.
The effects of androgens, antiandrogens, and other steroid hormones on growth of the human prostate cancer cell line LNCaP were studied. Despite the absence of receptors for progesterone and estradiol, the growth rate of the androgen responsive LNCaP-FGC cells increased when cultured in the presence of either estrogens or progestagens. In addition, most antiandrogens were also growth stimulators. This aberrant response was due to a threonine to alanine substitution at amino acid position 868 in the steroid binding domain of the androgen receptor (AR). Only the antiandrogen ICI 176,334 could block transcription and cell growth by the mutant receptor. By immunoprecipitation of the AR from LNCaP cells with the specific antibody F39.4.1 and Western blotting, three types of heat-shock proteins co-precipitated: hsp90, hsp70 and hsp56. This co-isolation could be prevented by pre-incubating the cells with androgens or with the antiandrogen hydroxyflutamide. Only the antiandrogen ICI 176,334 could block the effect of androgens on complex dissociation and prevent tight nuclear binding of the AR. Hydroxyflutamide could only inhibit tight nuclear binding of the wild-type AR. Therefore, in LNCaP cells the mutation in the steroid binding domain of the AR prevents a blockade of receptor function by most antiandrogens, but not by ICI 176,334, probably because of a different mechanism by which this compound blocks receptor function.
Veldscholte
J
J
Department of Endocrinology and Reproduction, Erasmus University Rotterdam, The Netherlands.
Berrevoets
C A
CA
Mulder
E
E
D000726:Androgen Antagonists / Q000494:pharmacology; D000728:Androgens / Q000502:physiology; D002455:Cell Division; D006801:Humans; D008297:Male; D009154:Mutation; D011471:Prostatic Neoplasms / Q000473:pathology*; D011944:Receptors, Androgen / Q000187:drug effects; D014407:Tumor Cells, Cultured
D000726:Androgen Antagonists; D000728:Androgens; D011944:Receptors, Androgen