mTOR Pathway in Papillary Thyroid Carcinoma: Different Contributions of mTORC1 and mTORC2 Complexes for Tumor...

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• The mammalian target of rapamycin (mTOR) pathway is frequently hyperactivated in thyroid cancer (TC).
• Previous studies linked phospho-mTOR to aggressive features and therapy resistance, while phospho-S6 (mTORC1 effector) indicated less aggressive disease in papillary thyroid carcinoma (PTC).
• The opposing roles of these markers suggested a potential preferential activation of the mTORC2 complex.

Purpose of the Study:

• To investigate the role of mTORC2 complex activation in thyroid cancer.
• To determine the association between mTORC2 signaling and clinicopathological features, including metastasis.
• To evaluate the impact of mTORC1 and mTORC2 inhibition on SLC5A5 mRNA expression.

Main Methods:

• Immunohistochemistry for phospho-AKT Ser473 (mTORC2 effector) was performed on 182 PTC samples.
• Samples were previously characterized for phospho-mTOR and phospho-S6 expression.
• Thyroid cancer cell lines were treated with RAD001 (mTORC1 inhibitor) and Torin2 (mTORC1/mTORC2 inhibitor) to assess effects on SLC5A5 mRNA levels.

Main Results:

• Phospho-AKT Ser473 expression positively correlated with phospho-mTOR expression.
• Nuclear phospho-AKT Ser473 was significantly associated with distant metastases.
• Torin2 treatment, but not RAD001, significantly increased SLC5A5 mRNA expression in TPC1 cells.

Conclusions:

• mTOR activation in PTC may preferentially activate the mTORC2 complex.
• Phospho-AKT Ser473, an mTORC2 effector, is implicated in distant metastization, therapy resistance, and SLC5A5 mRNA downregulation.
• Targeting mTORC2 may represent a therapeutic strategy for aggressive thyroid cancer.