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*PROGESTERONE
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*Prostate Cancer
The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 2 705-712
Copyright © 2003 by The Endocrine Society

Sex Hormone Metabolism in Prostate Cancer Cells during Transition to an Androgen-Independent State

Päivi Härkönen, Svea Törn, Riitta Kurkela, Katja Porvari, Anitta Pulkka, Aija Lindfors, Veli Isomaa and Pirkko Vihko

Biocenter Oulu and Research Center for Molecular Endocrinology, University of Oulu, FIN-90014 Oulu, Finland

Address all correspondence and requests for reprints to: Pirkko Vihko, M.D., Research Center for Molecular Endocrinology, P. O. Box 5000, University of Oulu, FIN-90014 Oulu, Finland. E-mail: pvihko{at}whoccr.oulu.fi.

The progression of prostate cancer during androgen deprivation therapy is a serious clinical problem. Little is known, however, about the mechanisms behind the transition of the disease to an androgen-independent stage. In the present report, we provide evidence of substantial changes in both estrogen and androgen metabolism during the transition of cultured prostate cancer LNCaP (lymph node carcinoma of the prostate) cells. The results of enzyme activity measurements performed using HPLC suggest that, related to the transition, there exists a remarkable decrease in the oxidative 17ß-hydroxysteroid dehydrogenase (17HSD) activity, whereas the reductive 17HSD activity seems to increase. Relative quantitative RT-PCR revealed that the decrease in oxidative activity largely coincided with the remarkable decrease in the expression of the HSD17B2 gene. Furthermore, the present data suggest that the observed increasing activity of 17HSD type 7 could lead to the increased intracellular production of 17ß-estradiol during disease progression. This was supported by the cDNA microarray screening results, which showed a considerable overexpression of several estrogen up-regulated genes in the LNCaP cell line variant that represents progressive prostate cancer. Because 17HSDs critically contribute to the control of bioavailability of active sex steroid hormones locally in the prostate, the observed variation in intraprostatic 17HSD activity might be predicted to be crucially involved in the regulation of growth and function of the organ.

This work was supported by funding provided by the Academy of Finland (projects 47630 and 50003) and National Technology Agency of Finland (40122/0).

Abbreviations: 3{alpha}A-diol, 5{alpha}-Androstane-3{alpha}, 17ß-diol; 3ßA-diol, 5{alpha}-androstane-3ß, 17ß-diol; A-dione, androstenedione; AI, androgen-independent; CFE, colony-forming efficiency; DHT, dihydrotestosterone; E1, estrone; E2, 17ß-estradiol; ER, estrogen receptor; EST, expressed sequence tag; FCS, fetal calf serum; HSD, hydroxysteroid dehydrogenase; LNCaP, lymph node carcinoma of the prostate; PSA, prostate-specific antigen; T, testosterone; tPA, tissue-type plasminogen activator.




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