PI3K/AKT Pathway and Its Mediators in Thyroid Carcinomas
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REVIEW ARTICLE
PI3K/AKT Pathway and Its Mediators in Thyroid Carcinomas Zahra Nozhat1,2 • Mehdi Hedayati1
Ó Springer International Publishing Switzerland 2015
Abstract 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
& Mehdi Hedayati [email protected]; [email protected] 1
Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
2
Biotechnology Department, School of Advanced Technology in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
activity induction with PI3K/AKT downstream mediators (e.g., mTOR) inhibition will be beneficial and promising in thyroid cancer treatment.
Key Points AKT overactivation in some of the thyroid cancers leads to the suppression of forkhead box O (FOXO) proteins and the mutations in the phosphatase and tensin homolog deleted on chromosome ten (PTEN) gene result in an increase in PI3K/AKT pathway activation. Thyroid cancer treatment via targeting FOXOs or PTEN has not been considered so far. It seems that the combination of targeting FOXOs and PTEN will develop a promising strategy in thyroid cancer treatment.
1 Introduction Although the thyroid carcinoma is not a prevalent disease, it is the most common malignancy of the endocrine glands [1]. There are four main histopathological subtypes of the thyroid cancers, with different cellular origins; these consist of papillary (PTC, 85 % of cases), follicular (FTC, 5–10 %), medullary (MTC, 5 %) and anaplastic (ATC, 1 %) cancers [2]. PTC and FTC, the differentiated forms of thyroid cancer, arise from thyroid follicular cells [3], whereas the origin of medullary thyroid carcinoma is p
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