Endocrinology, doi:10.1210/en.2006-0937
Endocrinology Vol. 148, No. 3 942-947
Copyright © 2007 by The Endocrine Society
AKT in Thyroid Tumorigenesis and Progression
Motoo Shinohara,
Yun Jae Chung,
Motoyasu Saji and
Matthew D. Ringel
Divisions of Endocrinology and Oncology and Thyroid Cancer Unit, Department of Internal Medicine, The Ohio State University College of Medicine and Arthur G. James Comprehensive Cancer Center, Columbus, Ohio 43210
Address all correspondence and requests for reprints to: Matthew D. Ringel, M.D., Associate Professor of Medicine, Divisions of Endocrinology and Oncology, The Ohio State University College of Medicine, 445D McCampbell Hall, 1581 Dodd Drive, Columbus, Ohio 43210. E-mail: matthew.ringel{at}osumc.edu.
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Abstract
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AKT (protein kinase B) is a central signaling molecule in the phosphatidyl inositol 3-kinase pathway that is frequently activated in human cancer. AKT activation regulates energy metabolism, apoptosis, proliferation, and migration in many cell systems. In thyroid cancer, AKT activation is involved in tumorigenesis, particularly in both inherited and sporadic forms of follicular thyroid cancer. Phosphatidyl inositol 3-kinase and AKT signaling also appear to play an important role in progression of both papillary and follicular cancers. In this review, the role of AKT in thyroid cancer development and progression are discussed with a focus on areas of current debate in the literature.
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Introduction
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CONSTITUTIVE OR ENHANCED signaling through classical tyrosine kinase-activated pathways is common in thyroid cancer. Activating mutations of BRAF and RET/PTC rearrangements are particularly common in papillary thyroid cancer (PTC) and mutations in RAS and PTEN, and gene rearrangements involving PPAR
occur frequently in follicular thyroid cancers (FTC) (1). In addition to these well-defined genetic causes of thyroid cancer, overexpression and activation of a variety of tyrosine kinase receptors, mutations in the p53 gene, activation of phosphatidylinositol 3-kinase (PI3K), and Wnt signaling, and expression of angiogenic factors and receptors all are common in progressive thyroid cancers, suggesting that they are late-stage events. Based on clinical correlation and experimental in vitro and in vivo data, the Ras/RAF and PI3K/AKT signal transduction cascades each play key regulatory roles both in thyroid tumor formation and progression. In this review, the mechanisms responsible for and the consequences of AKT [protein kinase B (PKB)] activation in thyroid cancer will be discussed. In addition, there will be a focus on new and/or controversial areas that require further exploration in defining the role of AKT in thyroid cancer biology.
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AKT Signaling
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AKT, also known as PKB, is a central signaling molecule in the PI3K pathway. Figure 1
outlines the classical pathway of activation for AKT that involves interactions between the pleckstrin homology domain of AKT with 3-OH phosphoinositides generated by PI3K activity for membrane localization and subsequent phosphorylation at the critical threonine 308 site (for AKT 1) by phosphoinositide-dependent kinase 1 and at the ser 473 via autophosphorylation or other kinases for maximal activation (2). Phosphatase and tensin homolog (PTEN) is a protein with lipid phosphatase activity that removes 3-OH groups from phosphoinositides, thereby reducing AKT cytosolic localization and subsequent activation. Thus, increased PI3K activity or reduced PTEN activity results in enhanced AKT activity.
Once activated, AKT phosphorylates numerous targets in the cytosol in which it interacts with chaperone proteins including heat shock protein 90; adapter protein containing pleckstrin homology domain, phosphotyrosine-binding domain, and leucine zipper region (APPL); and others (3, 4). Activated AKT is also transported to the nucleus through uncertain mechanisms by which it also phosphorylates target proteins (5). AKT is exported from the nucleus via interactions with chromosome region maintenance protein (CRM)-1 at a nuclear export sequence localized in its kinase domain (6). Subcellular localization of AKT isoforms is a potentially important determinant of biological effects, as noted in the case of T-cell prolymphocytic leukemia caused by gene rearrangements in AKT chaperone protein T-cell leukemia (TCL)-1 that cause nuclear AKT accumulation that is necessary for malignant transformation (7).
Three AKT isoforms have been cloned in humans, each with significant homology but different tissue distributions. AKT 1 (PKB
) was initially cloned as a homolog to the viral AKT8 oncogene and is ubiquitously expressed (8, 9). AKT 1 knockout mice are viable but small in size (10, 11). By contrast, AKT 2 is preferentially expressed in insulin-responsive tissues, and AKT 2 knockout mice develop type 2 diabetes (12). AKT 3 gene expression is limited to the brain, heart, and kidneys, with expression noted in a number of poorly differentiated cancers (13, 14). In the normal thyroid, all three AKT isoforms are expressed, but AKT 1 and 2 are the predominant isoforms at both the mRNA and protein levels (15). The precise role of each isoform in thyroid cell biology is not certain. As discussed later in this manuscript, there has been a number of recent findings that have demonstrated physiologically important AKT isoform-specific cellular functions.
Downstream targets of AKT regulate apoptosis, proliferation, and cell cycle progression, cytoskeletal stability and motility, and energy metabolism as reviewed in detail previously (2, 16). AKT phosphorylation of target proteins requires a minimal peptide binding sequence, Arg-Xaa-Arg-Yaa-Zaa-Ser/Thr-Hyd, in which Xaa represents any amino acid, Yaa and Zaa represent small, nonglycine amino acids, and Hyd represents a hydrophobic amino acid. Termination of AKT activity occurs indirectly at the level of PI3K through the lipid phosphatase activity of PTEN (17) and directly by the activity of phosphatases at the thr 308 and ser 473 sites, including protein phosphatase 2A (18) and pleckstrin homology domain leucine-rich repeat protein phosphatase (19), respectively. AKT activity can also be disrupted by altering its stability through interference with heat shock protein 90 protein binding, a feature that has been exploited with clinical intent (20).
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AKT Activation in Follicular Thyroid Tumorigenesis
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A role for AKT signaling in thyroid tumorigenesis was first recognized when loss of PTEN expression was identified to be the genetic cause of Cowden’s syndrome, an autosomal dominant multiple hamartoma syndrome in which more than 50% of patients develop thyroid neoplasia (21). Nearly all thyroid tumors in Cowden’s syndrome are nonfunctioning follicular neoplasias, including both benign adenomas and FTCs. The thyroid tumors in both patients and PTEN null mice are associated with enhanced AKT activation (22). Recently it has been demonstrated that cross-breeding of heterozygous PTEN+/– mice with AKT 1 null mice results in reduced tendency to develop thyroid cancer, confirming a key role for AKT in follicular tumorigenesis in Cowden’s syndrome (23). It is likely, however, that other PI3K-regulated pathways are also important in FTC development in Cowden’s syndrome.
The importance of AKT signaling in sporadic FTC has subsequently been demonstrated by several groups. Ringel et al. (15) demonstrated that sporadic FTCs are characterized by increased expression of AKT 1 and AKT 2 and have increased levels of total AKT activity in comparison with normal tissue specimens. Potential mechanisms for this increase activity have been explored subsequently. Vasko et al. (24) reported that increased AKT activity in FTCs correlated with either activating mutations in RAS or PPAR/PAX8 gene rearrangements. In addition, Wu et al. (25) reported a relatively high frequency of PI3KCA gene amplifications in FTCs. This group, as well as Garcia-Rosten et al. (26) reported a low incidence of mutations in the PI3KCA gene in sporadic FTCs. Reduced expression of PTEN mRNA and protein, either through mutations or other mechanisms, including promoter methylation, has been described in FTCs (27, 28, 29). Finally, the development of FTC in mice with generalized overexpression of a thyroid hormone-resistant mutant form of the thyroid hormone receptor-ß, TRßpv/pv, using a knock-in approach appears to be mediated by enhanced PI3K signaling and subsequent AKT activity (30). Thus, AKT activation appears to be a common early event in FTC tumor initiation in both rare inherited and sporadic forms of the disease.
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AKT in Papillary Thyroid Tumorigenesis
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The gene mutations responsible for the development of most PTCs have been characterized and include activating mutations in BRAF, most commonly in sporadic cases in adults; RET/PTC rearrangements, particularly in pediatric and radiation-induced PTCs; RAS mutations in follicular variant of PTC; and other less common abnormalities (1). The overall absence of overlap between these genetic changes in individual tumors, the ability of these oncogenes to all induce PTC in vivo via common pathways, and the similarities of expression patterns associated with each of these oncogenes convincingly demonstrate that activation of RAS-RAF-ERK is of primary importance in sporadic PTC development. In contrast, the role of PI3K/AKT signaling in PTC appears to be most prominent in tumor progression (see below).
When considering the role of PI3K/AKT in PTC tumorigenesis, it is operationally reasonable to separate tumors with BRAF mutations from those with either RET/PTC rearrangements or RAS mutations because BRAF mutants do not appear to activate the PI3K/AKT pathway, whereas RET/PTC and Ras coactivate both pathways. Indeed, in human thyroid cancers, cDNA microarray demonstrate that RET/PTC rearrangements are associated with expression of genes downstream of PI3K that differ from tumors with BRAF mutations (31). In addition, in comparison with tumors with mutations in BRAF, those with RAS mutations or RET/PTC rearrangements demonstrated activation of both ERK and AKT (24). In vitro, activation of PI3K/AKT plays an essential role in RET/PTC signaling and downstream cellular effects on migration and proliferation in both thyroid and nonthyroid cell systems (32, 33, 34). These effects appear to be through activation of PI3K and also by direct functional tyrosine phosphorylation of AKT Tyr315 (35). Moreover, in some cell systems, RET/PTC-mediated AKT activation leads to increased expression levels of other tyrosine kinase receptors, such as hepatocyte growth factor receptor (cMET) (36), or overexpression of key signaling molecules, such as insulin receptor substrate-2, that can further magnify its biological effects (37). The precise role of AKT in PTC development in vivo has not yet been fully elucidated.
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AKT Activation in Thyroid Cancer Progression
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PI3K signaling has been shown to play a central role in cancer cell proliferation, antiapoptosis, and motility. Enhanced AKT activity is associated with advanced tumor stage and progression for a number of different malignancies (38). In thyroid cancer, the association between increased AKT activity and tumor size and invasion has been demonstrated for both FTC and PTC, with the exception of tumors with BRAF activating mutations (39, 40). In addition, a broad role for PI3K signaling has been demonstrated for proliferation, survival, and invasion and motility for PTC, FTC, and anaplastic thyroid cancer cell lines in vitro. Thus, it appears that activation of AKT as well as other PI3K-regulated proteins, including p70S6 kinase and mammalian target of rapamycin (41, 42, 43, 44), play important roles in thyroid cell proliferation and cancer progression. Because patients with these more aggressive cancers account for most thyroid cancer-related deaths, there has been an interest in exploiting this role to develop novel therapies (16, 38). Several recent mechanistic observations from other malignancies strongly suggest that a more detailed understanding of the mechanisms of AKT in thyroid cancer progression are needed before taking this step.
Whereas it is unlikely that any single pathway is alone responsible for tumor progression, PI3K effectors, including AKT, appear to play an important role in this process in thyroid cancer. Pharmacological and molecular inhibition of PI3K and AKT isoforms has been demonstrated to reduce proliferation and motility in a number of human thyroid cancer cell lines in vitro. PI3K and more specific AKT inhibitors reduce thyroid cancer cell cycle progression at G2/M phase transition and are able to induce apoptosis, despite the overall resistance of poorly differentiated thyroid cells to apoptosis in general (45, 46). In addition, RET/PTC-induced cell motility and expression of osteopontin, a key regulator of epithelial-to-mesenchymal transition (EMT), has been shown to be mediated by PI3K and AKT (33). More recently the ability of peroxisomal proliferator-activated receptor- agonists to partially reverse EMT has been shown to be in part dependent on up-regulation of PTEN expression with subsequent inhibition of AKT activity (47).
In vivo, studies in the TRßpv/pv mouse that develops metastatic FTC-like thyroid cancer have demonstrated enhanced AKT activation in the primary and metastatic tumor tissue (30). Moreover, primary cultures from TRßpv/pv primary thyroid cancers display AKT-dependent cell motility in Boyden chambers, consistent with a role for AKT in metastasis in this model. The precise mechanisms by which AKT induces migration in thyroid cancer are an area of active study in a number of laboratories.
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Determinants of AKT Effects in Thyroid Cancer Progression
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AKT isoform specificity
Whereas nearly all studies in cancer cell cultures have demonstrated that AKT activity increases proliferation, it has recently become apparent that AKT effects on invasion and motility are more varied (48). The results appear to depend on the particular AKT isoform involved, the modified cDNA used to study the effects of constitutive activation, the cell type, and the inherent invasive capacity of the cell line. In fibroblasts, AKT 1 and/or AKT 1 and 3 expression have been shown to be necessary for cell motility in vitro using mouse embryonic fibroblasts (MEFs) derived from homozygous knock out mice. Saji et al. (6) reported that AKT 1–/– MEFs have a reduced ability to migrate in Boyden chamber assays in comparison with MEFs derived from wild-type littermate control mice. In addition, AKT 1–/– MEFs stably transfected with wild-type or constitutively activated forms of AKT 1 (phospho-mimicking at 308 and 473) regained the ability to migrate. Similar results were recently reported by Crean et al. (49), who demonstrated that the absence of both AKT 1 and 3 in MEFs block the ability of connective tissue growth factor to induce actin depolymerization and motility in comparison with wild-type MEFs. These results are consistent with earlier studies demonstrating a key role for AKT 1 in the induction and/or maintenance of a motile phenotype in poorly differentiated cancer cell models as has been reported using a number of cell lines from different tumor types.
In thyroid cancer cell lines, more motile fibroblastoid in vitro cell types such as NPA cells have been shown to have AKT 1-dependent cell migration (6). Whereas AKT 1 appears to be important for migration of other thyroid cancer cell lines, including the ARO and WRO lines, the degree of isoform-specific effects varies between the different cell systems (Saji, M., and M. D. Ringel, unpublished observations). Thus, even within a cancer type, the isoform specificity of the response appears variable depending on the cell line analyzed.
These results must be balanced against recent studies in differentiated epithelial mammary carcinoma cell lines demonstrating that AKT 1 inhibits migration, whereas AKT 2 appears to promote migration. For example, Liu et al. (50) reported in HMT-3522 and T4–2 mammary epithelial cancer cells that a constitutively membrane bound myristoylated AKT 1 isoform increased proliferation and anchorage independence, but reduced motility and invasion in vitro, and that, in xenografts, the tumor derived from these cells were larger but less invasive than those expressing control vector. The ability of myristoylated AKT 1 to block migration in these mammary epithelial cells involved inhibition of Rho activity through phosphorylation and down-regulation of tuberous sclerosis (TSC)-2. In addition, tumors with low levels of both AKT 1 and TSC2 mRNA levels tended to metastasize earlier than other tumors, suggesting a role for the AKT1/TSC2 pathway in blocking human breast cancer progression. This was a follow-up study from an initial publication in which this group demonstrated that AKT 2, but not AKT 1, is responsible for IGF-I-induced migration, growth, and EMT in breast cancer cells (51). Similar results regarding the ability of AKT 1 to inhibit invasiveness in mammary epithelial cell lines were reported by Yoel-Lerner et al. (52) in MDA-MB-435 and 231 cells. In this study, the ability of AKT 1 to reduce migration was mediated by inhibition of nuclear factor of activated T cells-1, a nuclear transcription factor known to be involved in cell motility. Finally, studies comparing the breast cancers that develop in ERbB2/AKT 1 double transgenic mice in comparison with the ERbB2 single transgenic mice demonstrate that the double-transgenic model develops larger, but less invasive breast cancers (53). Earlier studies have suggested that AKT 2 expression may lead to a more invasive phenotype in breast cancer cells (54), but the studies in MEFs demonstrate that AKT 2 is alone insufficient to maintain a migratory phenotype and small interfering (si) RNA studies in NPA thyroid cancer demonstrate a prominent role for Akt1 in cell motility in vitro.
What then are the possible reasons for these differences in cellular responses to AKT 1? It is attractive to speculate that the difference in migratory response of cells to AKT 1 activity relates to the degree of fibroblastoid nature of the cells being studied (see Fig. 2). A fibroblastoid appearance of cancer cells is often associated with EMT and an invasive phenotype that are late stage events for most cancers. Thus, as has been suggested (48, 50), it is possible that early in tumorigenesis, AKT 1 induces proliferation but inhibits invasion through interactions with TSC2 and nuclear factor of activated T cells-1. As cancers progress, the cells become more poorly differentiated and invasive, undergoing EMT. In these cells, AKT 1 serves not only as a positive regulator of growth but also motility, perhaps due to loss of the normal epithelial control mechanisms. Clearly more data are required to test this hypothesis. A second possibility is tissue specificity in expression of AKT substrates, such as TSC2, neurofibromatosis type 1, and others involved in cytoskeletal organization and motility result in cell type-specific effects of AKT 1 or other isoforms. Whereas there are many other potential reasons for these interesting results, a third possibility is preferential activation of nuclear targets in invasive cells due to the propensity of AKT to be located in the nucleus in invasive cancers and the importance of nuclear AKT targeting in T-cell prolymphocytic leukemia (5, 18).
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FIG. 2. Model of signaling activation in thyroid cancer. In FTC, early events induced by specific genetic abnormalities predominantly or partially involve AKT activation. In PTC, ERK activation is the primary early event for most tumors. In differentiated epithelial cells, AKT 1 appears to be primarily involved in tumor growth and may inhibit invasive potential, but this is not yet tested. The role of other AKT isoforms is not as well defined in early stage cancers to date, although AKT 2 might induce invasion. After secondary genetic or environmental alterations, perhaps induced by the specific oncogene, thyroid cancer cells become more dedifferentiated, potentially completing EMT and/or developing metastatic potential. In this circumstance, AKT is both proproliferative and induces motility and, along with numerous other pathways, promotes tumor progression; a partial list is provided. VEGF, Vascular endothelial growth factor; NF, nuclear factor; Opn, osteopontin; Vim, vimentin.
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AKT subcellular localization
As noted above, once activated, AKT is bound to chaperone proteins and interacts with effectors in the cytosol, it also enters the nucleus, in which it has been shown to interact with substrate proteins that may, in part, differ from those in the cytosol (5, 18). In thyroid and breast cancer, a tendency for prominent enhancement of nuclear AKT activity in the cancer cells at the leading edge of in invasive fronts has been reported (24, 55, 56). These same tumor regions have high levels of cytosolic AKT-phosphorylated p27, further supporting the observation of enhanced AKT activity. Experimentally, similar correlations have been made in the invasive fronts of primary FTCs in the TRßpv/pv mice (30). Based on the recent data regarding AKT 1 activity in breast cancer cell motility, it is of interest that among the AKT isoforms, immunoactive AKT 1 localization correlated with the nuclear activated AKT. The data demonstrating that this event occurred most prominently at the leading edge of primary tumors or in metastasis support the hypothesis that AKT 1 nuclear activation in thyroid cancer may be a late-stage event.
In vitro studies subsequently demonstrated that NPA thyroid cancer cell invasion was associated with nuclear localization of activated AKT and cytosolic p27 (24). Moreover, similar to the human tumors, AKT 1 immunoactivity, but not AKT 2 or 3, colocalized with the activated nuclear AKT. Functionally, AKT 1 siRNA reduced cell migration to a greater degree than AKT 2 or 3 siRNAs; and p27 siRNA inhibited migration (6). The functional relationship between AKT activation and subsequent phosphorylation and cytoplasmic localization and retention of p27 and cell motility is further supported by studies in thyroid and breast cancer cells (43, 56, 57, 58).
The mechanisms for AKT nuclear import remain uncertain because neither AKT nor its chaperones contain recognizable nuclear localization signals. The AKT sequence contains several putative nuclear export sequences predicted to bind CRM-1. Saji et al. (6) demonstrated that AKT 1 physically interacts with CRM-1 and that this interaction can be disrupted by mutation of the leucine-rich nuclear export signal (NES) in amino acid residues 272–284. Interestingly, overexpression of this mutant with reduced CRM-1 binding results in preferential nuclear localization with persistent kinase-activity, although this may not be generalizable for all cell systems (59). Expression of this 
NES mutant form of AKT 1 in AKT 1–/– MEFs was sufficient to induce migration in a similar manner to wild-type AKT 1 or mobile phospho-mimicking constitutively activated forms of AKT 1, suggesting the nuclear AKT activity is sufficient to induce cell migration. Interestingly, there was no effect of this construct on cell growth. Experimentally, it is important to note that these experiments were most effective when performed using the less bulky hemaglutinin epitope tag rather than a green fluorescent protein tag related to increased apoptosis in cells transfected with nuclear localized green fluorescent protein in control experiments (Saji, M., and M. D. Ringel, unpublished observations). Finally, specific reduction of p27 levels using siRNA in both thyroid cancer cells and AKT 1–/– MEFs reexpressing nuclear or activated forms of AKT 1 was sufficient to inhibit invasion in vitro. These data suggest that in fibroblasts, nuclear predominant AKT 1 activity is sufficient to induce migration in a p27-dependent manner. Whether nuclear export-deficient forms of AKT 1 exert different effects from myristoylated AKT 1 in more differentiated epithelial cell models has not yet been reported.
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Summary
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AKT plays an important role in thyroid tumorigenesis and progression. Activation of AKT is central to FTC development as is demonstrated in Cowden’s syndrome and sporadic FTC tumor samples. In PTC, its role in tumor development is less clear. However, AKT signaling appears to play an important role in thyroid cancer progression in a manner that may differ from its effects early in tumorigenesis, depending on the tumor type, particular isoform of AKT that is activated, localization of AKT within the cell, and repertoire of downstream AKT effectors available for phosphorylation. A more complete understanding of these processes is required before targeting AKT, or one if its isoforms, for therapy in thyroid cancer because they may be crucial for predicting which patients may benefit from treatment.
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Footnotes
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This work was supported by grants from the National Institutes of Health (RO1 CA102572) and American Cancer Society (RSG 02030-01-CNE) (to M.D.R.).
Disclosure Summary: All authors have nothing to declare.
First Published Online August 31, 2006
Abbreviations: CRM, Chromosome region maintenance protein; EMT, epithelial-to-mesenchymal transition; FTC, follicular thyroid cancer; MEF, mouse embryonic fibroblast; PI3K, phosphatidylinositol 3-kinase; PKB, protein kinase B; PTC, papillary thyroid cancer; PTEN, phosphatase and tensin homolog; si, small interfering; TSC, tuberous sclerosis.
Received July 13, 2006.
Accepted for publication August 21, 2006.
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Abstract
Introduction
