Triiodothyronine Attenuates Prostate Cancer Progression Mediated by β-Adrenergic Stimulation

Evangelina Delgado-González, Ana Alicia Sánchez-Tusie, Giapsy Morales, Carmen Aceves, Brenda Anguiano

Prostate cancer cells are responsive to adrenergic and thyroid stimuli. It is well established that β-adrenergic activation (PKA/CREB) promotes cancer progression, but the role of thyroid hormones (TH) is poorly understood. We analyzed the effects of β-adrenergic stimulation (isoproterenol, ISO), and/or TH 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 weeks with ISO (200 μg/day), triiodothyronine (T3, 2.5 μg/day), or both. ISO alone reduced tumor growth but increased tumor expression of cAMP response element (CRE)-dependent genes (real-time PCR, chromogranin A, neuron specific enolase, survivin, VEGF, uPA, and 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 μM ISO or 100 nM 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 co-administration of ISO+T4. In contrast, 10 nM 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 T4/T3 could be relevant for prostate cancer progression.