Sex hormone metabolism in prostate cancer cells during transition to an androgen-independent state.
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 17 beta-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 17 beta-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.
Härkönen
Päivi
P
Biocenter Oulu and Research Center for Molecular Endocrinology, University of Oulu, FIN-90014 Oulu, Finland.
Törn
Svea
S
Kurkela
Riitta
R
Porvari
Katja
K
Pulkka
Anitta
A
Lindfors
Aija
A
Isomaa
Veli
V
Vihko
Pirkko
P
D015067:17-Hydroxysteroid Dehydrogenases / Q000235:genetics* / Q000378:metabolism*; D000728:Androgens / Q000737:chemistry / Q000378:metabolism; D004967:Estrogens / Q000737:chemistry / Q000378:metabolism; D038681:Follistatin / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D012739:Gonadal Steroid Hormones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D010739:Phospholipase D / Q000235:genetics; D011374:Progesterone / Q000737:chemistry / Q000378:metabolism; D011471:Prostatic Neoplasms; D010959:Tissue Plasminogen Activator / Q000235:genetics; D014407:Tumor Cells, Cultured
D000728:Androgens; D004967:Estrogens; D038681:Follistatin; D012739:Gonadal Steroid Hormones; D011374:Progesterone; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase; D010739:Phospholipase D; D010959:Tissue Plasminogen Activator