PI3K/AKT Pathway and Its Mediators in Thyroid Carcinomas

Thyroid malignancies are the most common endocrine system carcinomas, with four histopathological forms. The phosphoinositide 3-kinase-protein kinase B/AKT (PI3K-PKB/AKT) pathway is one of the most critical molecular signaling pathways implicated in key cellular processes. Its continuous activation by several aberrant receptor tyrosine kinases (RTKs) and genetic mutations in its downstream effectors result in high cell proliferation in a broad number of cancers, including thyroid carcinomas. In this review article, the role of different signaling pathways of PI3K/AKT in thyroid cancers, with the emphasis on the PI3K/AKT/mammalian target of rapamycin (mTOR), PI3K/AKT/forkhead box O (FOXO) and PI3K/AKT/phosphatase and tensin homolog deleted on chromosome ten (PTEN) pathways, and various therapeutic strategies targeting these pathways have been summarized. In most of the in vitro studies, agents inhibiting mTOR in monotherapy or in combination with chemotherapy for thyroid malignancies have been introduced as promising anticancer therapies. FOXOs and PTEN are two outstanding downstream targets of the PI3K/AKT pathway. At the present time, no study has been undertaken to consider thyroid cancer treatment via FOXOs and PTEN targeting. According to the critical role of these proteins in cell cycle arrest, it seems that a treatment strategy based on the combination of FOXOs or PTEN activity induction with PI3K/AKT downstream mediators (e.g., mTOR) inhibition will be beneficial and promising in thyroid cancer treatment.