Triiodothyronine Attenuates Prostate Cancer Progression Mediated by β-Adrenergic Stimulation

Prostate cancer cells are responsive to adrenergic and thyroid stimuli. It is well established that beta-adrenergic activation (protein kinase A [PKA]/cAMP response element binding protein [CREB]) promotes cancer progression, but the role of thyroid hormones is poorly understood. We analyzed the effects of beta-adrenergic stimulation (isoproterenol [ISO]) and/or thyroid hormone on neuroendocrine (NE) differentiation and cell invasion, using in vivo (LNCaP tumor) and in vitro models (LNCaP and DU145 human cells). Nude mice were inoculated with LNCaP cells and were treated for 6 wks with ISO (200 mu g/d), triiodothyronine (T3, 2.5 mu g/d) or both. ISO alone reduced tumor growth but increased tumor expression of cAMP response element (CRE)-dependent genes (real-time polymerase chain reaction, chromogranin A, neuron-specific enolase, survivin, vascular endothelial growth factor [VEGF], urokinase plasmin activator [uPA] and metalloproteinase-9 [MMP-9]) and some proteins related to NE differentiation and/or invasiveness (synaptophysin, VEGF, pCREB). T3 reduced tumor growth and prevented the overexpression of ISO-stimulated factors through a pCREB-independent mechanism. In low invasive LNCaP cells, 50 mu mol/L ISO or 100 nmol/L thyroxine (T4) induced the acquisition of NE-like morphology (phase-contrast microscopy), increased VEGF secretion (ELISA) and invasive capacity (Transwell assay), but no synergistic effects were observed after the coadministration of ISO + T4. In contrast, 10 nmol/L T3 alone had no effect, but it prevented the NE-like morphology and invasiveness stimulated by ISO. None of these treatments had any effect on highly invasive DU145 cells. In summary, this study showed that ISO and T4 increase cancer progression, and T3 attenuates ISO-stimulated progression. Further studies are required to determine if changes in the ratio of T4/T3 could be relevant for prostate cancer progression.