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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 ?PV/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?

SUBMITTER: Saji M

PROVIDER: S-EPMC7591514 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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

Saji Motoyasu M Kim Caroline S CS Wang Chaojie C Zhang Xiaoli X Khanal Tilak T Coombes Kevin K La Perle Krista K Cheng Sheue-Yann SY Tsichlis Philip N PN Ringel Matthew D MD

Scientific reports 20201027 1

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-/ ...[more]

PMID: 33110146

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AKT isoform-specific expression and activation across cancer lineages.

Project description:BackgroundAberrant AKT activation is prevalent across human cancer lineages, providing an important therapeutic target. AKT comprises three isoforms that mediate critical non-redundant, even opposing functions in cancer pathophysiology. Therefore, targeting specific AKT isoforms in particular cancers may be more effective than pan-AKT inhibition while avoiding disadvantages of pan-AKT inhibition. Currently, AKT isoform-specific expression and activation in cancer are not clearly characterized.MethodsWe systematically characterized AKT isoform-specific expression and activation in 211 cancer cell lines derived from different lineages and genetic backgrounds using a reverse-phase protein array platform.ResultsWe found that phosphorylation, but not expression, of AKT1 and AKT2 was coordinated in most but not all cells. Different cancer lineages displayed differential AKT1 and AKT2 expression and phosphorylation. A PIK3CA hotspot mutation H1047R but not E545K was associated with selective activation of AKT2 but not AKT1.ConclusionsOur study identified and validated AKT isoform-specific expression and phosphorylation in certain cell lines and demonstrated that genetic changes can affect AKT isoform-specific activation. These results provide a more precise understanding of AKT isoform-specific signaling and, in addition, facilitate AKT isoform targeting for personalized cancer therapies.

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AKT isoform specific signaling

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Akt1 deficiency delays tumor progression, vascular invasion, and distant metastasis in a murine model of thyroid cancer.

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PTEN regulated PI3K-p110 and AKT isoform plasticity controls metastatic prostate cancer progression.

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Phosphoproteomics screen reveals akt isoform-specific signals linking RNA processing to lung cancer.

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PTEN regulated PI3K-p110 and AKT isoform plasticity controls metastatic prostate cancer progression

Project description:PTEN loss, one of the most frequent mutations in prostate cancer (PC), is presumed to drive disease progression through AKT activation. However, two transgenic PC models with Akt activation plus Rb loss exhibited different metastatic development: Pten/RbPE:-/- mice produced systemic metastatic adenocarcinomas with high AKT2 activation, whereas RbPE:-/- mice deficient for the Src-scaffolding protein, Akap12, induced high-grade prostatic intraepithelial neoplasias and indolent lymph node dissemination, correlating with upregulated phosphotyrosyl PI3K-p85α. Using PC cells isogenic for PTEN, we show that PTEN-deficiency correlated with dependence on both p110β and AKT2 for in vitro and in vivo parameters of metastatic growth or motility, and with downregulation of SMAD4, a known PC metastasis suppressor. In contrast, PTEN expression, which dampened these oncogenic behaviors, correlated with greater dependence on p110α plus AKT1. Our data suggest that metastatic PC aggressiveness is controlled by specific PI3K/AKT isoform combinations influenced by divergent Src activation or PTEN-loss pathways.

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