Endocrine Abstracts (2016) 40 OC1 | DOI: 10.1530/endoabs.40.OC1

A new chemotherapy combination (U0126+SN50) potentiates apoptosis in thyroid cancer but induced survival in normal thyroid

Joana S Rodrigues1, Angela R Garcia-Rendueles1, Maria E R Garcia-Rendueles9, Maria Suarez Fariña1, Sihara Perez-Romero1, Ignacio Bernabeu4, Javier Rodriguez-Garcia5, Laura Fugazzola6, Toshiyuki Sakai7, Fang Liu8, Jose Cameselle-Teijeiro3, Susana B Bravo2 & Clara V Alvarez1


1Centre for Investigations in Molecular Medicine and Chronic Disease (CIMUS) and Institute of Investigaciones Sanitarias (IDIS), Group of Endocrine Neoplasia and Differentiation, Departments of 2Proteomics, Department of 3Pathology, Department of 4Proteomics Endocrinology and Department of 5Proteomics Clinical Biochemistry, University Hospital of Santiago de Compostela (CHUS), University of Santiago de Compostela (USC), A Coruña, Spain; 6Endocrine Unit, Fondazione Policlinico IRCCS, Milano, Italy; 7Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan; 8Center for Advanced Biotechnology and Medicine, Susan Lehman Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, Brunswick, New Jersey, USA; 9Memorial Sloan-Kettering Cancer Center, New York City, New York, USA.


Papillary thyroid carcinoma (PTC), the most frequent thyroid cancer, has low proliferation but no apoptosis, presenting frequent lymph-node metastasis (Ordonez et al., 2004).

SMAD3 has two opposite phosphorylation sites: the TGF-βRI–induced C-terminal Serine SMAD3 phosphorylation and the phosphorylation induced by CDK2 (T8, T179 and S213) and ERK (T179, S204, S208) (Wang et al. 2005, Matsuura et al. 2005).

In our previous studies, we have demonstrated that in normal thyroid, TGF-β/SMAD represses p27/CDKN1B gene, activating CDK2-dependent T179-SMAD3 phosphorylation to induce p50 NFκB-dependent BAX upregulation and apoptosis.

In thyroid cancer, oncogene activation prevents TGF-β/SMAD-dependent p27 repression, and CDK2/SMAD3 phosphorylation, leading to p65 NFκB upregulation which represses BAX, induces cyclin D1 and prompts TGF-β-dependent growth.

The p27/CDKN1B gene is downregulated by SMAD3 in normal thyroid but not in thyroid cancer. This could be used because both PTC groups (those originated in oncogenic BRAF and RAS or similar mutations) have a high activation of the MEK/ERK pathway (Agrawal et al. 2014). A high MEK/ERK activity phosphorylates SMADs at the linker region preventing p27 downregulation by TGF-β in thyroid cancer cells, blocking the apoptotic pathway.

The aim of this work is to study if combined therapies based on the p27/SMAD/NFkB pathway could be use in future clinical trials.

MEK inhibitor U0126 was used alone or combined with NFkB inhibitor (SN50) in thyroid cancer cells and in normal thyroid cells cultured in human homeostatic conditions (h7H) (Bravo et al. 2013).

Combined ERK and p65 NFkB inhibitors reduce p27 and potentiate apoptosis in thyroid cancer while survival in normal thyroid.

Our study suggests that a combination of chemotherapy (U0126+SN50) could kill cancer cells but prevent death in normal thyroid cells. This could open a new avenue to treat thyroid cancer patients after surgery preventing recurrences and shifts to malignancy.