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PI3K/AKT Pathway and Its Mediators in Thyroid Carcinomas

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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.

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References

  1. National Cancer Institute. SEER Stat Fact Sheet. Thyroid cancer. 2013. http://seer.cancer.gov/statfacts/html/thyro.html. Accessed 28 Oct 2013.

  2. Rajhbeharrysingh U, Taylor M, Milas M. Medical therapy for advanced forms of thyroid cancer. Surg Clin N Am. 2014;94:541–71.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  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  CAS  Google Scholar 

  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  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Scopa CD. Histopathology of thyroid tumors. An overview. Hormones. 2004;3:100–10.

    Article  PubMed  Google Scholar 

  10. Xing M. Molecular pathogenesis and mechanisms of thyroid cancer. Nat Rev Cancer. 2013;13:184–99.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  11. Hemmings BA, Restuccia DF. PI3K-PKB/Akt Pathway. Cold Spring Harb Perspect Biol. 2012;4:a011189.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Alexandraki KI, Kaltsas G. Gastroenteropancreatic neuroendocrine tumors: new insights in the diagnosis and therapy. Endocrine. 2012;41:40–52.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  15. Liu P, Cheng H, Roberts TM, Zhao JJ. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov. 2009;8:627–44.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  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.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  20. Yuan TL, Cantley LC. PI3K pathway alterations in cancer: variations on a theme. Oncogene. 2008;27:5497–510.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  21. Xing M. Genetic alterations in the phosphatidylinositol-3 kinase/Akt pathway in thyroid cancer. Thyroid. 2010;20:697–706.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  22. Saji M, Ringel MD. The PI3K-Akt-mTOR pathway in initiation and progression of thyroid tumors. Mol Cell Endocrinol. 2010;321:20–8.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  23. Stokoe D. The phosphoinositide 3-kinase pathway and cancer. Expert Rev Mol Med. 2005;7:1–22.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  27. Carracedo A, Pandolfi PP. The PTEN-PI3K pathway: of feedbacks and cross-talks. Oncogene. 2008;27:5527–41.

    Article  PubMed  CAS  Google Scholar 

  28. Burgering BM, Coffer PJ. Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction. Nature. 1995;376:599–602.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  30. Testa JR, Tsichlis PN. AKT signaling in normal and malignant cells. Oncogene. 2005;24(50):7391–3.

    Article  PubMed  CAS  Google Scholar 

  31. Staal SP, Hartley JW. Thymic lymphoma induction by the AKT8 murine retrovirus. J Exp Med. 1988;167(3):1259–64.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  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  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  39. Fruman DA, Rommel C. PI3K and cancer: lessons, challenges and opportunities. Nat Rev Drug Discov. 2014;13:140–56.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  40. Samuels Y, Ericson K. Oncogenic PI3K and its role in cancer. Curr Opin Oncol. 2006;18:77–82.

    Article  PubMed  CAS  Google Scholar 

  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  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  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  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  46. Xing M. Recent advances in molecular biology of thyroid cancer and their clinical implications. Otolaryngol Clin N Am. 2008;41:1135–46.

    Article  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  48. Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer. 2002;2:489–501.

    Article  PubMed  CAS  Google Scholar 

  49. Weichhart T. Mammalian target of rapamycin: a signaling kinase for every aspect of cellular life. Methods Mol Biol. 2012;821:1–14.

    Article  PubMed  CAS  Google Scholar 

  50. Laplante M, Sabatini DM. mTOR signaling at a glance. J Cell Sci. 2009;122:3589–94.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  55. Sabatini DM. mTOR and cancer: insights into a complex relationship. Nat Rev Cancer. 2006;6:729–34.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  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.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  62. Nicholson KM, Anderson NG. The protein kinase B/Akt signalling pathway in human malignancy. Cell Signal. 2002;14:381–95.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  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  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  67. Wells SA, Santoro M. Targeting the RET pathway in thyroid cancer. Clin Cancer Res. 2009;15:7119–23.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  71. Porta C, Paglino C, Mosca A. Targeting PI3K/Akt/mTOR Signaling in Cancer. Front Oncol. 2014;4:64.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  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.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  77. Xu PZ, Chen ML, Jeon SM, Peng XD, Hay N. The effect Akt2 deletion on tumor development in Pten(+/−) mice. Oncogene. 2012;31(4):518–26.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  82. Paes JE, Ringel MD. Dysregulation of the phosphatidylinositol 3-kinase pathway in thyroid neoplasia. Endocrinol Metab Clin N Am. 2008;37:375–87.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  85. Bader AG, Kang S, Zhao L, Vogt PK. Oncogenic PI3K deregulates transcription and translation. Nat Rev Cancer. 2005;5:921–9.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  88. Salih DA, Brunet A. FoxO transcription factors in the maintenance of cellular homeostasis during aging. Curr Opin Cell Biol. 2008;20(2):126–36.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  90. Zhang X, Tang N, Hadden TJ, Rishi AK. Akt, FoxO and regulation of apoptosis. Biochim Biophys Acta. 2011;1813:1978–86.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  95. Souza EC, Ferreira AC, Carvalho DP. The mTOR protein as a target in thyroid cancer. Expert Opin Ther Targets. 2011;15:1099–112.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  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.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  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.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  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.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  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.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  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.

    PubMed  CAS  PubMed Central  Google Scholar 

  106. Kondo T, Ezzat S, Asa SL. Pathogenetic mechanisms in thyroid follicular-cell neoplasia. Nat Rev Cancer. 2006;6(4):292–306.

    Article  PubMed  CAS  Google Scholar 

  107. Nikiforova MN, Nikiforov YE. Molecular diagnostics and predictors in thyroid cancer. Thyroid. 2009;19(12):1351–61.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  118. Gustafson S, Zbuk K, Scacheri C, Eng C. Cowden syndrome. Semin Oncol. 2007;34:428–34.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

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  1. Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Zahra Nozhat & Mehdi Hedayati

  2. Biotechnology Department, School of Advanced Technology in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Zahra Nozhat

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  1. Zahra Nozhat
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Nozhat, Z., Hedayati, M. PI3K/AKT Pathway and Its Mediators in Thyroid Carcinomas. Mol Diagn Ther 20, 13–26 (2016). https://doi.org/10.1007/s40291-015-0175-y

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