mTOR Pathway in Papillary Thyroid Carcinoma: Different Contributions of mTORC1 and mTORC2 Complexes for Tumor Behavior and SLC5A5 mRNA Expression

• Main Author: Tavares, Catarina
• Publication Date: 2018
• Other Authors: Eloy, Catarina, Melo, Miguel, Gaspar da Rocha, Adriana, Pestana, Ana, Batista, Rui, Bueno Ferreira, Luciana, Rios, Elisabete, Sobrinho-Simões, Manuel, Soares, Paula
• Format: Article
• Language: eng
• Source: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Download full: http://hdl.handle.net/10316/107692; https://doi.org/10.3390/ijms19051448
• topic: mTOR; thyroid cancer; sodium iodide symporter (NIS)/SLC5A5; Carcinoma, Papillary; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Phosphorylation; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-akt; RNA, Messenger; Symporters; TOR Serine-Threonine Kinases; Thyroid Cancer, Papillary; Thyroid Neoplasms; Signal Transduction

The mammalian target of rapamycin (mTOR) pathway is overactivated in thyroid cancer (TC). We previously demonstrated that phospho-mTOR expression is associated with tumor aggressiveness, therapy resistance, and lower mRNA expression of SLC5A5 in papillary thyroid carcinoma (PTC), while phospho-S6 (mTORC1 effector) expression was associated with less aggressive clinicopathological features. The distinct behavior of the two markers led us to hypothesize that mTOR activation may be contributing to a preferential activation of the mTORC2 complex. To approach this question, we performed immunohistochemistry for phospho-AKT Ser473 (mTORC2 effector) in a series of 182 PTCs previously characterized for phospho-mTOR and phospho-S6 expression. We evaluated the impact of each mTOR complex on SLC5A5 mRNA expression by treating cell lines with RAD001 (mTORC1 blocker) and Torin2 (mTORC1 and mTORC2 blocker). Phospho-AKT Ser473 expression was positively correlated with phospho-mTOR expression. Nuclear expression of phospho-AKT Ser473 was significantly associated with the presence of distant metastases. Treatment of cell lines with RAD001 did not increase SLC5A5 mRNA levels, whereas Torin2 caused a ~6 fold increase in SLC5A5 mRNA expression in the TPC1 cell line. In PTC, phospho-mTOR activation may lead to the activation of the mTORC2 complex. Its downstream effector, phospho-AKT Ser473, may be implicated in distant metastization, therapy resistance, and downregulation of SLC5A5 mRNA expression.