Abstract C62: Triiodothyronine (T3) supplementation prevents the overexpresion of invasion factors induced by β-adrenergic stimulation in prostate cancer models
Authors: Delgado-González Evangelina , Aceves Carmen , Anguiano Brenda 
Published: May 2013

There are multiple pieces of evidence that the sympathetic nervous system and thyroid hormones play crucial roles in normal and cancerous development of tissues. It is well established that chronic β-adrenergic stimulation (cAMP-PKA-CREB pathway) is a risk factor for progression of prostate cancer because it promotes cell migration, tumor invasion, and metastasis. Moreover, studies in human prostate cancer cells (LNCaP) show that a high dose of adrenaline induces transdifferentiation of secretor epithelium into a neuroendocrine phenotype with high invasive potential. Although studies from our group have shown a direct relation between sympathetic-input and prostate T3 generation (which seems to be associated with epithelial differentiation that occurs at puberty), there is no evidence about T3 effects on the progression of prostate cancer. Studies in hepatic cancer show that T3 administration reverses the neoplastic lesions induced by a chemical carcinogen (differentiating effects). The aim of this study was to analyze, in models of prostate cancer (in vivo and in vitro), the effects of β-adrenergic stimulation, T3, or both on tumor progression. Nude mice (nu/nu, 8 weeks old) were subcutaneously transplanted with human prostate cancer cells (LNCaP). Two days later, the mice were implanted in the back with a controlled-release pellet of isoproterenol (ISO, β-adrenergic agonist, 200 μg/day), and T3 was administrated in the drinking water (2.5 μg/day). Single (ISO or T3) or combined treatments (ISO+T3) were maintained for 6 weeks, and body weight, tumor incidence, and tumor volume were registered every week. In prostate tumor, qRT-PCR was used to analyze the expression of genes related to angiogenesis (vascular endothelial growth factor, VEGF), invasion (urokinase plasmin activator, uPA; metalloproteinase 9, MMP9), and neuroendocrine phenotype (chromogranin A, CgA). The results showed that none of the treatments affected body weight. In the ISO and ISO + T3 groups, tumors appeared in week 3, while in control and T3 groups the onset of the tumors occurred by week 5. In comparison with the control group, ISO treatment decreased tumor growth, but increased the expression of VEGF, uPA, MMP9, and CgA (2-3 fold). These effects are consistent with the well known effects of β-adrenergic stimulation on the acquisition of the neuroendocrine phenotype (slowly proliferating but highly invasive tumors). T3 administration prevents the increase of VEGF, uPA, MMP9, and CgA expression induced by ISO. Administration of T3 alone did not modify the tumoral growth or gene expression mentioned above. Migration assays in vitro of LNCaP cells showed that ISO increased cell migration, and T3 prevented the ISO effect (ISO + T3). These findings suggest that T3 might inhibit the transcription of genes dependent on β-adrenergic stimulation in prostate cancer. Current studies are analyzing if the protective effects of T3 might be associated with CREB inactivation.

The authors are grateful to Guadalupe Delgado, Felipe Ortiz, and Martín García for their technical assistance. We thank Dr. Erika Rendón (Facultad de Medicina, UNAM) for her advice for the in vitro assays. Supported by CONACYT (78955, 87196, 127368), PAPIIT (IN201210).

Citation Format: Evangelina Delgado-González, Carmen Aceves, Brenda Anguiano. Triiodothyronine (T3) supplementation prevents the overexpresion of invasion factors induced by β-adrenergic stimulation in prostate cancer models [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C62.