Lithium stimulates proliferation in cultured thyrocytes by activating Wnt/β-catenin signalling

Abstract

Background: Lithium, clinically used in the treatment of bipolar disorders, is well known to induce thyroid growth. However, the mechanism involved is only incompletely characterized. Although it is conventionally believed that thyroid proliferation depends on the thyroid-stimulating hormone (TSH)/cAMP/cAMPresponseelementbinding protein (CREB) pathway, recent data indicate that Wnt/b-catenin signalling may be of critical importance. In other cell types lithium activates canonical Wnt signalling by GSK-3b inhibition, which in turn stabilizes cytosolic free b-catenin. Here we investigated the potential modulation of Wnt/b-catenin signalling under lithium treatment in primary and neoplastic human thyrocytes. Methods: Primary (S18) and neoplastic (NPA, FTC133) thyrocytes treated with and without LiCl were analysed using Western blotting, immunoprecipitation, reporter-gene assay, MTT proliferation assay and transfection studies. Results: LiCl dose-dependently inhibited GSK-3b, stabilized free b-catenin and inhibited b-catenin degradation. Furthermore, LiCl altered the assembly of adherens junction by upregulating the E-cadherin repressor, Snail, and downregulated E-cadherin expression. At a dose of 5 mM, LiCl significantly increased the proliferative potency of thyrocytes, which appeared to be mediated by b-catenin, since nuclear b-catenin stimulated T-cell factor/lymphoid enhancer factor (TCF/LEF)-mediated transcription and upregulated downstream targets like cyclin D1. To characterize the specificity of Wnt/b-catenin-driven thyrocyte proliferation, we transfected primary thyrocytes and FTC133 cells with dominant negative TCF4 to block Wnt-dependent pathways or with dominant negative CREB to inhibit the TSH/cAMP cascade. In cells transfected with dominant negative CREB lithium-stimulated proliferation was unchanged whereas blocking Wnt/b-catenin by dominant negative TCF4 reduced proliferation by approx. 50%. Conclusion: Our data indicate that Wnt/b-catenin signalling is of major importance in the control of lithium-dependent thyrocyte proliferation.

Take the Wnt out of the inflammatory sails: modulatory effects of Wnt in airway diseases

“…58 Therefore, LiCl has been widely used as a surrogate compound to assess the involvement of the Wnt/β-catenin pathway. [59][60][61][62][63][64] Interestingly, the current knowledge of the Wnt pathway can now explain clinical observation made even before the Wnt pathways have been described. Early case reports already demonstrated that treatment of patients suffering from chronic schizophrenia and asthma with LiCl not only reduced the manic episodes but also caused a reduction of asthma attacks and the use of asthma-specific medication, 65 and other clinical observations showed that stopping a long-lasting LiCl therapy in a patient-induced increased airway hyper-responsiveness and asthma symptoms.…”

Characterization of Wnt/β-catenin signaling in rhabdomyosarcoma

“…As activation of Wnt/bcatenin pathway decreases proliferation and increases myodifferentiation in RMS, activation of this pathway may be useful therapeutic tool in the management of aggressive alveolar RMS, for example, using lithium chloride to inhibit GSK-3b. 14 There appears to be a tumour-suppressive role for Wnt/ -catenin signaling pathway in ARMS that needs to be investigated further. 28,29 In summary, this study has shown that Wnt proteins are expressed in tissue samples from alveolar and embryonal RMS, and has provided in vitro data indicating that the pathway may be functionally active.…”

“…12,13 The Wnt pathway is crucial in cell proliferation, cell migration, polarity and cell death. 14,15 Dysregulation of Wnt/b-catenin signaling facilitates cancer invasion and metastases in various tumours. 16,17 Inactive Wnt signaling results in cytoplasmic b-catenin associating with a multimolecular complex containing casein kinase a, glycogen synthase kinase-3b (GSK-3b), axin and adenomatosis polyposis coli (APC) protein.…”

“…Active Wnt signaling promotes the downstream signaling cascade and the activation of disheveled (Dsh) protein, which in turn inactivates GSK3b. [14][15][16][17][18] This allows b-catenin to translocate into the nucleus where it binds to T-cell factor/lymphoid-enhancing factor (TCF/LEF), leading to activation of target genes including c-Myc, 19 cyclin D1, 20,21 c-Jun, 22 Slug 23,24 and Cox2. 25 In addition, TCF/LEF/b-catenin complex may cooperate with factors activated by other signaling pathways to modulate cellular remodeling.…”

The Pivotal Roles of GSK3β in Glioma Biology

“…GSK3 inhibition promotes translocation of dephosphorylated and stabilizedcatenin to the nucleus and its interaction with transcription factors, resulting in the induction of genes responsible for cell proliferation. Lithium chloride (LiCl), a chemical GSK3 inhibitor, significantly increased the proliferative potency of thyrocytes that appeared to be mediated by -catenin (Rao et al, 2005). Similarly, the small molecule 6-bromoindirubin-3′-oxime (BIO), a specific inhibitor for GSK3, promotes proliferation in mammalian cardiomyocytes by elevated -catenin activity (Tseng et al, 2006).…”