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Endocrine Abstracts (2020) 70 AEP865 | DOI: 10.1530/endoabs.70.AEP865

ECE2020 Audio ePoster Presentations Thyroid (144 abstracts)

Targeting RAC1 signaling to potentiate the positive effect of MAPK pathway inhibition on radioiodine uptake

Márcia Faria 1,2,3 , Rita Domingues 1,4 , Maria João Bugalho 1,5 , Paulo Matos 2,3 & Ana Luísa Silva 1,4


1Serviço de Endocrinologia, Hospital de Santa Maria- CHULN. EPE, Lisboa, Portugal; 2BioISI- Biosystems and Integrative Sciences Institute, Faculdade de Ciências da Universidade de Lisboa, Lisboa, Portugal; 3Departamento de Genética Humana, Instituto Nacional de Saúde Doutor Ricardo Jorge, Lisboa, Portugal; 4ISAMB- Instituto de Saúde Ambiental, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal; 5Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal


Introduction: The Sodium Iodide Symporter (NIS) is responsible for active transport of iodide into thyroid follicular cells, enabling the use of radioactive iodine (RAI) for treatment of metastatic disease. Still, a significant proportion of patients with advanced forms of thyroid cancer (TC) became refractory to RAI therapy. Defective NIS expression is the main reason for impaired iodide uptake in TC and NIS downregulation has been associated with several pathways linked to malignant transformation. Activation of MAPK pathway has emerged as a key signaling implicated in thyroid tumorigenesis and NIS downregulation has been associated with the overactivation of this pathway. Consistently, several strategies aiming at inhibiting the MAPK-pathway have been developed with the goal of increasing the uptake of iodide in refractory tumors to allow treatment with RAI. Nevertheless, the use of MAPK-pathway inhibitors only partly restored NIS expression in several experimental models. Thus, therapeutic strategies directed to additional targets implicated in NIS upregulation could provide an additional level of adjuvant therapeutic intervention to enhance RAI uptake and increase clinical effectiveness. We have recently shown that the small GTPase RAC1 has a positive impact on TSH-induced NIS expression and iodide uptake in thyroid cells.

Objective: We evaluated whether the recovery of NIS expression induced by inhibition of the MAPK pathway can be increased by potentiating RAC1 activity in thyroid cell systems.

Methods: NRASQ61R and BRAFV600E mutantswere ectopically expressed in the thyroid follicular cell lines PCCL3 and FRTL5 by lentiviral transduction. The papillary TC-derived BCPAP cell line, in which the MAPK-pathway is constitutively activated by the BRAFV600E mutation, was also used. Cell lines were transfected with GFP-empty vector or GFP-G12V RAC1 expressing constructs, in the presence or absence of the MEK inhibitor AZD-6244. The impact of AZD-6244 treatment and ectopic overexpression of the constitutively active G12V-RAC1 mutant on NIS transcript levels was addressed by RT-qPCR.

Results: Treatment of both PCCL3 and FRTL5 cell lines with AZD-6244 consistently increased NIS transcript levels, overcoming the negative effect on NIS induced by NRAQ61R and BRAFV600E overexpression. Interestingly, inhibition of RAC1 signaling was able to partially block the AZD-6244-mediated positive impact on NIS expression. A relevant increase in NIS levels was also observed following treatment of BCPAP cancer cells with AZD-6244. Notably, this increase was considerably improved by the presence of active RAC1.

Conclusions: Overall, our data support the potential of the stimulation of RAC1 activity in enhancing NIS expression in the thyroid context.

Volume 70

22nd European Congress of Endocrinology

Online
05 Sep 2020 - 09 Sep 2020

European Society of Endocrinology 

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