Akt isoform-specific effects on thyroid cancer development and progression in a murine thyroid cancer model

Abstract

The Akt family is comprised of three unique homologous proteins with isoform-specific effects, but isoform-specific in vivo data are limited in follicular thyroid cancer (FTC), a PI3 kinase-driven tumor. Prior studies demonstrated that PI3K/Akt signaling is important in thyroid hormone receptor βPV/PV knock-in (PV) mice that develop metastatic thyroid cancer that most closely resembles FTC. To determine the roles of Akt isoforms in this model we crossed Akt1−/−, Akt2−/−, and Akt3−/− mice with PV mice. Over 12 months, thyroid size was reduced for the Akt null crosses (p < 0.001). Thyroid cancer development and local invasion were delayed in only the PVPV-Akt1 knock out (KO) mice in association with increased apoptosis with no change in proliferation. Primary-cultured PVPV-Akt1KO thyrocytes uniquely displayed a reduced cell motility. In contrast, loss of any Akt isoform reduced lung metastasis while vascular invasion was reduced with Akt1 or 3 loss. Microarray of thyroid RNA displayed incomplete overlap between the Akt KO models. The most upregulated gene was the dendritic cell (DC) marker CD209a only in PVPV-Akt1KO thyroids. Immunohistochemistry demonstrated an increase in CD209a-expressing cells in the PVPV-Akt1KO thyroids. In summary, Akt isoforms exhibit common and differential functions that regulate local and metastatic progression in this model of thyroid cancer.

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“…AKT, a protein kinase that regulates cell survival and apoptosis, is phosphorylated by PDK1 ( 33 , 34 ). As shown in Fig.…”

IRS1 promotes thyroid cancer metastasis through EMT and PI3K/AKT pathways

“…Akt isoform specifically promoted the development of thyroid cancer in a mouse thyroid cancer model. 34 The PI3K/AKT pathway is one of the most critical molecular signaling pathways involved in key cellular processes of thyroid malignancies. 35 It has been reported that IRS proteins may become biomarkers of PI3K pathway activity and serve as necessary biomarkers to guide targeted therapy.…”

“…Akt isoform specifically promoted the development of thyroid cancer in a mouse thyroid cancer model 34 . The PI3K/AKT pathway is one of the most critical molecular signaling pathways involved in key cellular processes of thyroid malignancies 35 .…”

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“…Activating mutations in genes encoding these protein kinases have been detected in FTCs, PDTCs and ATCs [ 53 , 55 , 56 ]. Murine TC model-based studies have shown that AKT1 is the primary promoter of TC development and local invasion, while vascular invasion and metastatic progression are dependent predominantly on AKT1 and AKT3, and to a lesser extent, on AKT2 [ 57 , 58 ].…”