The aim of this study was to characterize the type of 5′-deiodinase activity in the prostate of pubescent rats (7–8 weeks), to establish its distribution in the lobes (ventral, dorsolateral, and anterior), and to analyze its modulation by prolactin (PRL), testosterone, dihydrotestosterone (DHT), and 17β-estradiol (E2). Our results showed that the enzymatic activity was highly susceptible to inhibition by 6-n-propyl-2-thiouracil and gold thioglucose, its preferential substrate was reverse tri-iodothyronine (rT3), it exhibited a low dithiothreitol requirement (5 mM), and the apparent K m and V max values for substrate (rT3) were approximately 0.25 μM and 9.0 pmol liberated/mg protein per hour, respectively. All these characteristics indicate the preferential expression of type 1 deiodinase (D1), which was corroborated by demonstrating the presence of D1 mRNA in prostate. D1 activity was detected in all lobes and was most abundant in the dorsolateral. Although we detected type 2 deiodinase (D2) mRNA expression, the D2 activity was almost undetectable. D1 activity was enhanced in animals with hyperthyroidism and hyperprolactinemia, in intact animals treated with finasteride (inhibitor of local DHT production), and in castrated animals with E2 replacement. In contrast, activity diminished in castrated animals with testosterone replacement. Our results suggest that thyroid hormones, PRL, and E2 exert a positive modulation on D1 activity, while testosterone and DHT exhibit an inhibitory effect. D1 activity may be associated with prostate maturation and/or function.
Brenda Anguiano, Alejandra López, Guadalupe Delgado, Carlos Romero, and Carmen Aceves
Ana Sánchez-Tusie, Carlos Montes de Oca, Julia Rodríguez-Castelán, Evangelina Delgado-González, Zamira Ortiz, Lourdes Álvarez, Carlos Zarco, Carmen Aceves, and Brenda Anguiano
Thyroxine (T4) promotes cell proliferation and tumor growth in prostate cancer models, but it is unknown if the increase in the triiodothyronine (T3)/T4 ratio could attenuate prostate tumor development. We assessed T3 effects on thyroid response, histology, proliferation, and apoptosis in the prostate of wild-type (WT) and TRAMP (transgenic adenocarcinoma of the mouse prostate) mice. Physiological doses of T3 were administered in the drinking water (2.5, 5 and 15 µg/100 g body weight) for 6 weeks. None of the doses modified the body weight or serum levels of testosterone, but all of them reduced serum T4 levels by 50%, and the highest dose increased the T3/T4 ratio in TRAMP. In WT, the highest dose of T3 decreased cyclin D1 levels (immunohistochemistry) but did not modify prostate weight or alter the epithelial morphology. In TRAMP, this dose reduced tumor growth by antiproliferative mechanisms independent of apoptosis, but it did not modify the intraluminal or fibromuscular invasion of tumors. In vitro, in the LNCaP prostate cancer cell line, we found that both T3 and T4 increased the number of viable cells (Trypan blue assay), and only T4 response was fully blocked in the presence of an integrin-binding inhibitor peptide (RGD, arginine-glycine-aspartate). In summary, our data show that the prostate was highly sensitive to physiological T3 doses and suggest that in vivo, an increase in the T3/T4 ratio could be associated with the reduced weight of prostate tumors. Longitudinal studies are required to understand the role of thyroid hormones in prostate cancer progression.