AKT activity is elevated in aggressive thyroid neoplasms where it promotes proliferation and invasion

Abstract

The PI3K/AKT/mTOR signaling pathway controls major cellular processes such as cell growth, proliferation and survival. Stimulation of this pathway leads to AKT phosphorylation and activation, resulting in phosphorylation of mTOR and myriad other targets. AKT upregulation has been implicated in thyroid cancer pathogenesis and is a candidate treatment target for patients with advanced disease that has not responded to traditional therapies. Here we evaluate a large series of benign and malignant thyroid tumors for AKT activity and intracellular distribution. We also deplete AKT from multiple thyroid cancer cell lines, including putative cancer stem cell lines, and measure the effect on proliferation and invasion in vitro. We show that active AKT has a predominantly nuclear distribution and its expression is highest in anaplastic thyroid carcinomas and papillary thyroid carcinomas, including encapsulated and invasive follicular variants. Depletion of AKT in thyroid carcinoma cell lines led to greatly reduced proliferative capacity and resulted in a reduction of invasive potential. A reduction in invasion was also observed in the cancer stem cell compartment. Targeting AKT activity in the clinical setting may slow the growth and spread of aggressive thyroid neoplasms, and target the tumor stem cell compartment.