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Molecular Diagnosis & Therapy
Published in: Molecular Diagnosis & Therapy 1/2016

01-02-2016 | Review Article

PI3K/AKT Pathway and Its Mediators in Thyroid Carcinomas

Authors: Zahra Nozhat, Mehdi Hedayati

Published in: Molecular Diagnosis & Therapy | Issue 1/2016

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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 activity induction with PI3K/AKT downstream mediators (e.g., mTOR) inhibition will be beneficial and promising in thyroid cancer treatment.
Literature
1.
2.
Rajhbeharrysingh U, Taylor M, Milas M. Medical therapy for advanced forms of thyroid cancer. Surg Clin N Am. 2014;94:541–71.PubMedCrossRef
3.
Carhill AA, Cabanillas ME, Jimenez C, Waguespack SG, Habra MA, Hu M, et al. The noninvestigational use of tyrosine kinase inhibitors in thyroid cancer: establishing a standard for patient safety and monitoring. J Clin Endocrinol Metab. 2013;98:31–42.PubMedPubMedCentralCrossRef
4.
Hedayati M, Nabipour I, Rezaei-Ghaleh N, Azizi F. Germline RET mutations in exons 10 and 11: an Iranian survey of 57 medullary thyroid carcinoma cases. Med J Malaysia. 2006;61:564–9.PubMed
5.
Hedayati M, Zarif Yeganeh M, Sheikhol Eslami S, Rezghi Barez S, Hoghooghi Rad L, Azizi F. Predominant RET germline mutations in exons 10, 11, and 16 in Iranian patients with hereditary medullary mhyroid carcinoma. J Thyroid Res. 2011;2011:264248.
6.
Ghazi AA, Bagheri M, Tabibi A, Sarvghadi F, Abdi H, Hedayati M, Pourafkari M, Tirgari F, Pourafkari M, Tirgari F, Yu R. Multiple endocrine neoplasia type 2A in an Iranian family. Clinical and genetic studies. Arch Iran Med. 2014;17:378–82.PubMed
7.
Alvandi E, Akrami SM, Chiani M, Hedayati M, Nayer BN, Tehrani MR, Nakhjavani M, Pedram M. Molecular analysis of the RET proto-oncogene key exons in patients with medullary thyroid carcinoma: a comprehensive study of the Iranian population. Thyroid. 2011;21:373–82.PubMedCrossRef
8.
Majidi M, Haghpanah V, Hedayati M, Khashayar P, Mohajeri-Tehrani MR, Larijani B. A family presenting with multiple endocrine neoplasia type 2B: a case report. J Med Case Rep. 2011;5:587.PubMedPubMedCentralCrossRef
9.
10.
11.
12.
Alexandraki KI, Kaltsas G. Gastroenteropancreatic neuroendocrine tumors: new insights in the diagnosis and therapy. Endocrine. 2012;41:40–52.PubMedCrossRef
13.
Motti ML, Califano D, Troncone G, De Marco C, Migliaccio I, Palmieri E, Pezzullo L, Palombini L, Fusco A, et al. Complex regulation of the cyclin-dependent kinase inhibitor p27kip1 in thyroid cancer cells by the PI3K/AKT pathway: regulation of p27kip1 expression and localization. Am J Pathol. 2005;166:737–49.PubMedPubMedCentralCrossRef
14.
Martini M, De Santis MC, Braccini L, Gulluni F, Hirsch E. PI3K/AKT signaling pathway and cancer: an updated review. Ann Med. 2014;46:372–83.PubMedCrossRef
15.
16.
Chen M, Zhang H, Wu J, Xu L, Xu D, Sun J. Promotion of the induction of cell pluripotency through metabolic remodeling by thyroid hormone triiodothyronine-activated PI3K/AKT signal pathway. Biomaterials. 2012;33:5514–23.PubMedPubMedCentralCrossRef
17.
Hou P, Liu D, Shan Y, Hu S, Studeman K, Condouris S, Wang Y, Trink A, El-Naggar AK, et al. Genetic alterations and their relationship in the phosphatidylinositol 3-kinase/Akt pathway in thyroid cancer. Clin Cancer Res. 2007;13:1161–70.PubMedCrossRef
18.
Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet. 2006;7:606–19.PubMedCrossRef
19.
Fresno Vara JA, Casado E, de Castro J, Cejas P, Belda-Iniesta C, González-Barón M. PI3K/Akt signalling pathway and cancer. Cancer Treat Rev. 2004;30:193–204.PubMedCrossRef
20.
21.
22.
23.
24.
Yoshioka K, Yoshida K, Cui H, Wakayama T, Takuwa N, Okamoto Y, et al. Endothelial PI3K-C2α, a class II PI3K, has an essential role in angiogenesis and vascular barrier function. Nat Med. 2012;18(10):1560–9.PubMedCrossRef
25.
Chew CL, Lunardi A, Gulluni F, Ruan DT, Chen M, Salmena L, et al. In vivo role of INPP4B in tumor and metastasis suppression through regulation of PI3K-AKT signaling at endosomes. Cancer Discov. 2015;5(7):740–51.PubMedCentralCrossRef
26.
Franco I, Gulluni F, Campa CC, Costa C, Margaria JP, Ciraolo E, et al. PI3K class II α controls spatially restricted endosomal PtdIns3P and Rab11 activation to promote primary cilium function. Dev Cell. 2014;28(6):647–58.PubMedPubMedCentralCrossRef
27.
Carracedo A, Pandolfi PP. The PTEN-PI3K pathway: of feedbacks and cross-talks. Oncogene. 2008;27:5527–41.PubMedCrossRef
28.
Burgering BM, Coffer PJ. Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction. Nature. 1995;376:599–602.PubMedCrossRef
29.
Fayard E, Tintignac LA, Baudry A, Hemmings BA. Protein kinase B/Akt at a glance. J Cell Sci. 2005;118(Pt 24):5675–8.PubMedCrossRef
30.
Testa JR, Tsichlis PN. AKT signaling in normal and malignant cells. Oncogene. 2005;24(50):7391–3.PubMedCrossRef
31.
Staal SP, Hartley JW. Thymic lymphoma induction by the AKT8 murine retrovirus. J Exp Med. 1988;167(3):1259–64.PubMedCrossRef
32.
Staal SP. Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2: amplification of AKT1 in a primary human gastric adenocarcinoma. Proc Nat Acad Sci USA. 1987;84(14):5034–7.PubMedPubMedCentralCrossRef
33.
Jones PF, Jakubowicz T, Pitossi FJ, Maurer F, Hemmings BA. Molecular cloning and identification of a serine/threonine protein kinase of the second-messenger subfamily. Proc Natl Acad Sci USA. 1991;88(10):4171–5.
34.
Coffer PJ, Woodgett JR. Molecular cloning and characterisation of a novel putative protein-serine kinase related to the cAMP-dependent and protein kinase C families. Eur J Biochem. 1992;205(3):1217.PubMed
35.
Hanada M, Feng J, Hemmings BA. Structure, regulation and function of PKB/AKT–a major therapeutic target. Biochim Biophys Acta. 2004;1697:3–16.PubMedCrossRef
36.
Feng J, Park J, Cron P, Hess D, Hemmings BA. Identification of a PKB/Akt hydrophobic motif Ser-473 kinase as DNA-dependent protein kinase. J Biol Chem. 2004;279(39):41189–96.PubMedCrossRef
37.
Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005;307(5712):1098–101.PubMedCrossRef
38.
Sozopoulos E, Litsiou H, Voutsinas G, Mitsiades N, Anagnostakis N, Tseva T, Patsouris E, Tseleni-Balafouta S. Mutational and immunohistochemical study of the PI3K/Akt pathway in papillary thyroid carcinoma in Greece. Endocr Pathol. 2010;21:90–100.PubMedCrossRef
39.
40.
41.
Song MS, Salmena L, Pandolfi PP. The functions and regulation of the PTEN tumour suppressor. Nat Rev Mol Cell Biol. 2012;13:283–96.PubMed
42.
Bai D, Ueno L, Vogt PK. Akt-mediated regulation of NFkappaB and the essentialness of NFkappaB for the oncogenicity of PI3K and Akt. Int J Cancer. 2009;125(12):2863–70.PubMedPubMedCentralCrossRef
43.
Ringel MD, Hayre N, Saito J, Saunier B, Schuppert F, Burch H, Bernet V, Burman KD, Kohn LD, Saji M. Overexpression and overactivation of Akt in thyroid carcinoma. Cancer Res. 2001;61:6105–11.PubMed
44.
Wang Y, Hou P, Yu H, Wang W, Ji M, Zhao S, Yan S, Sun X, Liu D, Shi B, Zhu G, Condouris S, Xing M. High prevalence and mutual exclusivity of genetic alterations in the PI3K/Akt pathway in thyroid tumors. J Clin Endocrinol Metab. 2007;92(6):2387–90.PubMedCrossRef
45.
Wu G, Mambo E, Guo Z, Hu S, Huang X, Gollin SM, Trink B, Ladenson PW, Sidransky D, Xing M. Uncommon mutation, but common amplifications, of the PIK3CA gene in thyroid tumors. J Clin Endocrinol Metab. 2005;90(8):4688–93.PubMedCrossRef
46.
Xing M. Recent advances in molecular biology of thyroid cancer and their clinical implications. Otolaryngol Clin N Am. 2008;41:1135–46.CrossRef
47.
Santarpia L, Myers JN, Sherman SI, Trimarchi F, Clayman GL, El-Naggar AK. Genetic alterations in the Ras/Raf/mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt signaling pathways in the folliicular variant of papillary thyroid carcinoma. Cancer. 2010;116:2974–83.PubMedCrossRef
48.
Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer. 2002;2:489–501.PubMedCrossRef
49.
Weichhart T. Mammalian target of rapamycin: a signaling kinase for every aspect of cellular life. Methods Mol Biol. 2012;821:1–14.PubMedCrossRef
50.
51.
Sancak Y, Thoreen CC, Peterson TR, Lindquist RA, Kang SA, Spooner E, Carr SA, Sabatini DM. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell. 2007;25(6):903–15.PubMedCrossRef
52.
Peterson TR, Laplante M, Thoreen CC, Sancak Y, Kang SA, Kuehl WM, Gray NS, Sabatini DM. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell. 2009;137(5):873–86.PubMedPubMedCentralCrossRef
53.
Ma L, Chen Z, Erdjument-Bromage H, Tempst P, Pandolfi PP. Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell. 2005;121(2):179–93.PubMedCrossRef
54.
Faustino A, Couto JP, Pópulo H, Rocha AS, Pardal F, Cameselle-Teijeiro JM, Lopes JM, Sobrinho-Simões M, Soares P. mTOR pathway overactivation in BRAF mutated papillary thyroid carcinoma. J Clin Endocrinol Metab. 2012;97(7):E1139–49.PubMedCrossRef
55.
Sabatini DM. mTOR and cancer: insights into a complex relationship. Nat Rev Cancer. 2006;6:729–34.PubMedCrossRef
56.
Guigon CJ, Fozzatti L, Lu C, Willingham MC, Cheng SY. Inhibition of mTORC1 signaling reduces tumor growth but does not prevent cancer progression in a mouse model of thyroid cancer. Carcinogenesis. 2010;31(7):1284–91.PubMedPubMedCentralCrossRef
57.
Guigon CJ, Zhao L, Willingham MC, Cheng SY. PTEN deficiency accelerates tumour progression in a mouse model of thyroid cancer. Oncogene. 2009;28:509–17.PubMedPubMedCentralCrossRef
58.
Ahmed M, Hussain AR, Bavi P, Ahmed SO, Al Sobhi SS, Al-Dayel F, Uddin S, Al-Kuraya KS. High prevalence of mTOR complex activity can be targeted using Torin2 in papillary thyroid carcinoma. Carcinogenesis. 2014;35(7):1564–72.PubMedCrossRef
59.
Liu J, Brown RE. Morphoproteomics demonstrates activation of mTOR pathway in anaplastic thyroid carcinoma: a preliminary observation. Ann Clin Lab Sci. 2010;40(3):211–7.PubMed
60.
Borders EB, Bivona C, Medina PJ. Mammalian target of rapamycin: biological function and target for novel anticancer agents. Am J Health Syst Pharm. 2010;67:2095–106.PubMedCrossRef
61.
Harrington LS, Findlay GM, Gray A, Tolkacheva T, Wigfield S, Rebholz H, et al. The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins. J Cell Biol. 2004;166(2):213–23.PubMedPubMedCentralCrossRef
62.
Nicholson KM, Anderson NG. The protein kinase B/Akt signalling pathway in human malignancy. Cell Signal. 2002;14:381–95.PubMedCrossRef
63.
Nave BT, Ouwens M, Withers DJ, Alessi DR, Shepherd PR. Mammalian target of rapamycin is a direct target for protein kinase B: identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation. Biochem J. 1999;344:427–31.PubMedPubMedCentralCrossRef
64.
Sekulic A, Hudson CC, Homme JL, Yin P, Otterness DM, Karnitz LM, Abraham RT. A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells. Cancer Res. 2000;60:3504–13.PubMed
65.
Tamburrino A, Molinolo AA, Salerno P, Chernock RD, Raffeld M, Xi L, Gutkind JS, Moley JF, Wells SA Jr, Santoro M. Activation of the mTOR pathway in primary medullary thyroid carcinoma and lymph node metastases. Clin Cancer Res. 2012;18:3532–40.PubMedCrossRef
66.
Rapa I, Saggiorato E, Giachino D, Palestini N, Orlandi F, Papotti M, Volante M. Mammalian target of rapamycin pathway activation is associated to RET mutation status in medullary thyroid carcinoma. J Clin Endocrinol Metab. 2011;96:2146–53.PubMedCrossRef
67.
Wells SA, Santoro M. Targeting the RET pathway in thyroid cancer. Clin Cancer Res. 2009;15:7119–23.PubMedCrossRef
68.
Yeganeh MZ, Sheikholeslami S, Behbahani GD, Farashi S, Hedayati M. Skewed mutational spectrum of RET proto-oncogene Exon10 in Iranian patients with medullary thyroid carcinoma. Tumour Biol. 2015;36(7):5225–31.
69.
Yeganeh M, Sheikholeslami S, Hedayati M. RET proto oncogene mutation detection and medullary thyroid carcinoma prevention. Asian Pac J Cancer Prev. 2015;16:2107–17.PubMedCrossRef
70.
Manfredi GI, Dicitore A, Gaudenzi G, Caraglia M, Persani L, Vitale G. PI3K/Akt/mTOR signaling in medullary thyroid cancer: a promising molecular target for cancer therapy. Endocrine. 2015;48:363–70.PubMedCrossRef
71.
72.
Patil PB, Sreenivasan V, Goel S, Nagaraju K, Vashishth Sh, Gupta S, Garg K. Cowden syndrome—clinico-radiological illustration of a rare case. Contemp Clin Dent. 2013;4:119–23.PubMedPubMedCentralCrossRef
73.
Pilarski R, Eng C. Will the real Cowden syndrome please stand up (again)? Expanding mutational and clinical spectra of the PTEN hamartoma tumour syndrome. J Med Genet. 2004;4:323–6.CrossRef
74.
Smith JR, Marqusee E, Webb S, Nose V, Fishman SJ, Shamberger RC, Frates MC, Huang SA. Thyroid nodules and cancer in children with PTEN hamartoma tumor syndrome. J Clin Endocrinol Metab. 2011;96:34–7.PubMedCrossRef
75.
Podsypanina K, Ellenson LH, Nemes A, Gu J, Tamura M, Yamada KM, et al. Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems. Proc Natl Acad Sci USA. 1999;96(4):1563–8.PubMedPubMedCentralCrossRef
76.
Chen ML, Xu PZ, Peng XD, Chen WS, Guzman G, Yang X, Di Cristofano A, et al. The deficiency of Akt1 is sufficient to suppress tumor development in Pten+/− mice. Genes Dev. 2006;20(12):1569–74.PubMedPubMedCentralCrossRef
77.
78.
Yeager N, Klein-Szanto A, Kimura S, Di Cristofano A. Pten loss in the mouse thyroid causes goiter and follicular adenomas: insights into thyroid function and Cowden disease pathogenesis. Cancer Res. 2007;67:959–66.PubMedCrossRef
79.
Dahia PL, Marsh DJ, Zheng Z, Zedenius J, Komminoth P, Frisk T, et al. Somatic deletions and mutations in the Cowden disease gene, PTEN, in sporadic thyroid tumors. Cancer Res. 1997;57(21):4710–3.PubMed
80.
Halachmi N, Halachmi S, Evron E, Cairns P, Okami K, Saji M, et al. Somatic mutations of the PTEN tumor suppressor gene in sporadic follicular thyroid tumors. Genes Chromosomes Cancer. 1998;23(3):239–43.PubMedCrossRef
81.
Bruni P, Boccia A, Baldassarre G, Trapasso F, Santoro M, Chiappetta G, Fusco A, Viglietto G. PTEN expression is reduced in a subset of sporadic thyroid carcinomas: evidence that PTEN-growth suppressing activity in thyroid cancer cells mediated by p27kip1. Oncogene. 2000;19(28):3146–55.PubMedCrossRef
82.
Paes JE, Ringel MD. Dysregulation of the phosphatidylinositol 3-kinase pathway in thyroid neoplasia. Endocrinol Metab Clin N Am. 2008;37:375–87.CrossRef
83.
Vilgelm A, Lian Z, Wang H, et al. Akt-mediated phosphorylation and activation of estrogen receptor alpha is required for endometrial neoplastic transformation in pten+/− mice. Cancer Res. 2006;66:3375–80.PubMedCrossRef
84.
Kofuji S, Kimura H, Nakanishi H, Nanjo H, Takasuga S, Liu H. INPP4B Is a PtdIns(3,4,5)P3 phosphatase that can act as a tumor suppressor. Cancer Discov. 2015;5(7):730–9.PubMedCrossRef
85.
Bader AG, Kang S, Zhao L, Vogt PK. Oncogenic PI3K deregulates transcription and translation. Nat Rev Cancer. 2005;5:921–9.PubMedCrossRef
86.
Tzivion G, Dobson M, Ramakrishnan G. FoxO transcription factors; regulation by AKT and 14-3-3 proteins. Biochim Biophys Acta. 2011;1813:1938–45.PubMedCrossRef
87.
Becker T, Loch G, Beyer M, Zinke I, Aschenbrenner AC, Carrera P, et al. FOXO-dependent regulation of innate immune homeostasis. Nature. 2010;463(7279):369–73.PubMedCrossRef
88.
89.
Guertin DA, Stevens DM, Thoreen CC, Burds AA, Kalaany NY, Moffat J, Brown M, Fitzgerald KJ, Sabatini DM. Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev Cell. 2006;11(6):859–71.PubMedCrossRef
90.
Zhang X, Tang N, Hadden TJ, Rishi AK. Akt, FoxO and regulation of apoptosis. Biochim Biophys Acta. 2011;1813:1978–86.PubMedCrossRef
91.
Hu MC, Lee DF, Xia W, Golfman LS, Ou-Yang F, Yang JY. IkappaB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. Cell. 2004;117(2):225–37.PubMedCrossRef
92.
Yang JY, Zong CS, Xia W, Yamaguchi H, Ding Q, Xie X, et al. ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation. Nat Cell Biol. 2008;10(2):138–48.PubMedPubMedCentralCrossRef
93.
Karger S, Weidinger C, Krause K, Sheu SY, Aigner T, Gimm O, Schmid KW, Dralle H, Fuhrer D. FOXO3a: a novel player in thyroid carcinogenesis? Endocr Relat Cancer. 2008;16:189–99.PubMedCrossRef
94.
Zaballos MA, Santisteban P. FOXO1 controls thyroid cell proliferation in response to TSH and IGF-I and is involved in thyroid tumorigenesis. Mol Endocrinol. 2012;27:50–62.PubMedCrossRef
95.
Souza EC, Ferreira AC, Carvalho DP. The mTOR protein as a target in thyroid cancer. Expert Opin Ther Targets. 2011;15:1099–112.PubMedCrossRef
96.
Liu D, Hou P, Liu Z, Wu G, Xing M. Genetic alterations in the phosphoinositide 3-kinase/Akt signaling pathway confer sensitivity of thyroid cancer cells to therapeutic targeting of Akt and mammalian target of rapamycin. Cancer Res. 2009;69:7311–9.PubMedPubMedCentralCrossRef
97.
Gild ML, Landa I, Ryder M, Ghossein RA, Knauf JA, Fagin JA. Targeting mTOR in RET mutant medullary and differentiated thyroid cancer cells. Endocr Relat Cancer. 2013;20:659–67.PubMedPubMedCentralCrossRef
98.
Liu R, Liu D, Xing M. The Akt inhibitor MK2206 synergizes, but perifosine antagonizes, the BRAF(V600E) inhibitor PLX4032 and the MEK1/2 inhibitor AZD6244 in the inhibition of thyroid cancer cells. J Clin Endocrinol Metab. 2012;97(2):E173–82.PubMedPubMedCentralCrossRef
99.
Jin N, Jiang T, Rosen DM, Nelkin BD, Ball DW. Dual inhibition of mitogen-activated protein kinase kinase and mammalian target of rapamycin in differentiated and anaplastic thyroid cancer. J Clin Endocrinol Metab. 2009;94(10):4107–12.PubMedPubMedCentralCrossRef
100.
Lin SF, Huang YY, Lin JD, Chou TC, Hsueh C, Wong RJ. Utility of a PI3K/mTOR inhibitor (NVP-BEZ235) for thyroid cancer therapy. PLoS One. 2012;7:e46726.PubMedPubMedCentralCrossRef
101.
Plews RL, Mohd Yusof A, Wang C, Saji M, Zhang X, Chen CS, Ringel MD, Phay JE. Novel Dual AMPK activator/mTOR inhibitor inhibits thyroid cancer cell growth. J Clin Endocrinol Metab. 2015;100:748–56.CrossRef
102.
Kandil E, Tsumagari K, Ma J, Abd Elmageed ZY, Li X, Slakey D, et al. Synergistic inhibition of thyroid cancer by suppressing MAPK/PI3K/AKT pathways. J Surg Res. 2013;184(2):898–906.PubMedCrossRef
103.
Barollo S, Bertazza L, Baldini E, Ulisse S, Cavedon E, Boscaro M, et al. The combination of RAF265, SB590885, ZSTK474 on thyroid cancer cell lines deeply impact on proliferation and MAPK and PI3K/Akt signaling pathways. Invest New Drugs. 2014;32(4):626–35.PubMedCrossRef
104.
Gunda V, Bucur O, Varnau J, Vanden Borre P, Bernasconi MJ, Khosravi-Far R, et al. Blocks to thyroid cancer cell apoptosis can be overcome by inhibition of the MAPK and PI3K/AKT pathways. Cell Death Dis. 2014;5:e1104.PubMedPubMedCentralCrossRef
105.
Bertazza L, Barollo S, Radu CM, Cavedon E, Simioni P, Faggian D, et al. Synergistic antitumour activity of RAF265 and ZSTK474 on human TT medullary thyroid cancer cells. J Cell Mol Med. 2015;19(9):2244–52.PubMedPubMedCentral
106.
Kondo T, Ezzat S, Asa SL. Pathogenetic mechanisms in thyroid follicular-cell neoplasia. Nat Rev Cancer. 2006;6(4):292–306.PubMedCrossRef
107.
Nikiforova MN, Nikiforov YE. Molecular diagnostics and predictors in thyroid cancer. Thyroid. 2009;19(12):1351–61.PubMedCrossRef
108.
Soares P, Trovisco V, Rocha AS, Lima J, Castro P, Preto A, et al. BRAF mutations and RET/PTC rearrangements are alternative events in the etiopathogenesis of PTC. Oncogene. 2003;22:4578–80.PubMedCrossRef
109.
Czarniecka A, Kowal M, Rusinek D, Krajewska J, Jarzab M, Stobiecka E, et al. The risk of relapse in papillary thyroid cancer (PTC) in the context of BRAF V600E mutation status and other prognostic factors. PLoS One. 2015;10(7):e0132821.PubMedPubMedCentralCrossRef
110.
Nikiforova MN, Lynch RA, Biddinger PW, Alexander EK, Dorn GW 2nd, Tallini G, et al. RAS point mutations and PAX8-PPARγ rearrangement in thyroid tumors: evidence for distinct molecular pathways in thyroid follicular carcinoma. J Clin Endocrinol Metab. 2003;88:2318–26.PubMedCrossRef
111.
Vasko V, Ferrand M, Di Cristofaro J, Carayon P, Henry JF, de Micco C. Specific pattern of RAS oncogene mutations in follicular thyroid tumors. J Clin Endocrinol Metab. 2003;88:2745–52.PubMedCrossRef
112.
Liu RT, Hou CY, You HL, Huang CC, Hock-Liew Chou FF, et al. Selective occurrence of ras mutations in benign and malignant thyroid follicular neoplasms in Taiwan. Thyroid. 2004;14:616–21.PubMedCrossRef
113.
Liu Z, Hou P, Ji M, Guan H, Studeman K, Jensen K, Vasko V, et al. Highly prevalent genetic alterations in receptor tyrosine kinases and phosphatidylinositol 3-kinase/akt and mitogen-activated protein kinase pathways in anaplastic and follicular thyroid cancers. J Clin Endocrinol Metab. 2008;93(8):3106–16.PubMedCrossRef
114.
Garcí-Rostán G, Costa AM, Pereira-Castro I, Salvatore G, Hernandez R, Hermsem MJ, et al. Mutation of the PIK3CA gene in anaplastic thyroid cancer. Cancer Res. 2005;65:10199–207.CrossRef
115.
Abubaker J, Jehan Z, Bavi P, Sultana M, Al-Harbi S, Ibrahim M, Al-Nuaim A, et al. Clinicopathological analysis of papillary thyroid cancer with PIK3CA alterations in a Middle Eastern population. J Clin Endocrinol Metab. 2008;93(2):611–8.PubMedCrossRef
116.
Santarpia L, El-Naggar AK, Cote GJ, Myers JN, Sherman SI. Phosphatidylinositol 3-kinase/akt and ras/raf-mitogen-activated protein kinase pathway mutations in anaplastic thyroid cancer. J Clin Endocrinol Metab. 2008;93(1):278–84.PubMedCrossRef
117.
Ricarte-Filho JC, Ryder M, Chitale DA, Rivera M, Heguy A, Ladanyi M, et al. Mutational profile of advanced primary and metastatic radioactive iodine-refractory thyroid cancers reveals distinct pathogenetic roles for BRAF, PIK3CA, and AKT1. Cancer Res. 2009;69(11):4885–93.PubMedPubMedCentralCrossRef
118.
119.
Miller KA, Yeager N, Baker K, Liao XH, Refetoff S, Di Cristofano A. Oncogenic Kras requires simultaneous PI3K signaling to induce ERK activation and transform thyroid epithelial cells in vivo. Cancer Res. 2009;69(8):3689–94.PubMedPubMedCentralCrossRef
120.
Hou P, Ji M, Xing M. Association of PTEN gene methylation with genetic alterations in the phosphatidylinositol 3-kinase/AKT signaling pathway in thyroid tumors. Cancer. 2008;113:2440–7.PubMedCrossRef
121.
Alvarez-Nuñez F, Bussaglia E, Mauricio D, Ybarra J, Vilar M, Lerma E, et al. PTEN promoter methylation in sporadic thyroid carcinomas. Thyroid. 2006;16:17–23.PubMedCrossRef
122.
Schagdarsurengin U, Gimm O, Dralle H, Hoang-Vu C, Dammann R. CpG island methylation of tumor-related promoters occurs preferentially in undifferentiated carcinoma. Thyroid. 2006;16:633–42.PubMedCrossRef
123.
Humudh EA, Al-Hindi HS, Almohanna M, Alzahrani AS. Absence of the most frequently reported mTOR mutations in thyroid neoplasms. Endocrine Society’s 96th Annual Meeting and Expo, Chicago, June 21–24, 2014.
Metadata
Title
PI3K/AKT Pathway and Its Mediators in Thyroid Carcinomas
Authors
Zahra Nozhat
Mehdi Hedayati
Publication date
01-02-2016
Publisher
Springer International Publishing
Published in
Molecular Diagnosis & Therapy / Issue 1/2016
Print ISSN: 1177-1062
Electronic ISSN: 1179-2000
DOI
https://doi.org/10.1007/s40291-015-0175-y

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