The PI3K/Akt Pathway in Tumors of Endocrine Tissues

Abstract

The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is a key driver in carcinogenesis. Defects in this pathway in human cancer syndromes such as Cowden's disease and Multiple Endocrine Neoplasia result in tumors of endocrine tissues, highlighting its importance in these cancer types. This review explores the growing evidence from multiple animal and in vitro models and from analysis of human tumors for the involvement of this pathway in the following: thyroid carcinoma subtypes, parathyroid carcinoma, pituitary tumors, adrenocortical carcinoma, phaeochromocytoma, neuroblastoma, and gastroenteropancreatic neuroendocrine tumors. While data are not always consistent, immunohistochemistry performed on human tumor tissue has been used alongside other techniques to demonstrate Akt overactivation. We review active Akt as a potential prognostic marker and the PI3K pathway as a therapeutic target in endocrine neoplasia.

Keywords: Akt/PKB kinases; adrenocortical carcinoma; gastroenteropancreatic neuroendocrine tumors; neuroblastoma; parathyroid tumors; phaeochromocytoma; pituitary tumors; thyroid tumors.

Figure 1

The PI3K/Akt pathway. Akt is recruited to the plasma membrane by phosphatidylinositol (3,4,5) trisphosphate (PIP3) produced from phosphatidylinositol (4, 5) bisphosphate (PIP2) by phosphatidylinositol 3-kinase (PI3K). PTEN is a phosphatase that promotes the reverse reaction. For activation, Akt is phosphorylated on Thr(308) by phosphoinositide-dependent kinase 1 (PDK1) and on Ser(473) primarily by the mTORC2 complex serving as PDK2. Upon full activation, Akt leaves the membrane and can adopt a nuclear or cytosolic localization. There are over 70 known molecular targets of the Akt kinase and the three targets believed to be the most important in carcinogenesis are shown. By phosphorylation of TSC2, Akt relieves its repressive effects on Rheb, resulting in downstream activation of the mTORC1 complex and enhanced RNA translation. GSK3β is a tumor suppressor, which targets a number of proliferation and survival regulators, including β-catenin and Mcl-1, and elevates activity of TSC2 [reviewed in Ref. (9)]. The family of forkhead transcription factors, FoxO, upregulates genes controlling cell cycle arrest and apoptosis and is inhibited by Akt. Whereas GSK3β and TSC2 can be phosphorylated by p-Akt(Thr308) in cells, phosphorylation at Ser(473) is critical to inactivate FoxO proteins [reviewed in Ref. (8)]. When these are phosphorylated they become transcriptionally inactive and subject to nuclear export. FoxO3A exhibits reduced nuclear expression in the majority of thyroid cancers in association with high levels of p-Akt(Ser473), and relevant FoxO3A downstream target genes have been identified in follicular rat thyroid cells (10) and subsequently in benign (FRTL-5) and malignant human thyrocytes (FTC-133) (11), as the CDKN1B gene encoding cyclin-dependent kinase inhibitor, p27^KIP1, and BCL2L11, encoding Bim, a pro-apoptotic member of the Bcl-2 family of proteins.

Figure 2

Percentage of tumors with mutations affecting MAPK or PI3K/Akt signaling pathways in thyroid cancer histotypes of follicular cell origin. Data obtained from the COSMIC, 2014 (32) database considering the top 20 mutations (accessed 16/12/2015). Numbers of samples: papillary, 19239; follicular, 253; anaplastic, 564; mixed papillary and follicular, 69.