Thyroid hormones differentially regulate phosphorylation of ERK and Akt via integrin <i>α</i>v<i>β</i>3 receptor in undifferentiated and differentiated PC‐12 cells

Barbakadze, Tamar; Natsvlishvili, Nino; Mikeladze, David

doi:10.1002/cbf.3013

Cited by 17 publications

(11 citation statements)

References 22 publications

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“…It has been shown that GSK3B leads to VDAC phosphorylation and consequent displacing of HK from mitochondria (42). As it has been shown that TH treatment increases Akt and ERK phosphorylation in several cell models (59, 62, 63, 64), we expected to observe in our hyperthyroidism model a situation where more GSK3B is phosphorylated and, therefore, inhibited. Thus, phosphorylated VDAC levels would probably be lower, favoring a greater HK association with mitochondria.…”

Section: Discussionmentioning

confidence: 75%

Thyroid states regulate subcellular glucose phosphorylation activity in male mice

Peçanha

Santos

da‐Silva

2017

Endocrine Connections

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The thyroid hormones (THs), triiodothyronine (T3) and thyroxine (T4), are very important in organism metabolism and regulate glucose utilization. Hexokinase (HK) is responsible for the first step of glycolysis, catalyzing the conversion of glucose to glucose 6-phosphate. HK has been found in different cellular compartments, and new functions have been attributed to this enzyme. The effects of hyperthyroidism on subcellular glucose phosphorylation in mouse tissues were examined. Tissues were removed, subcellular fractions were isolated from eu- and hyperthyroid (T3, 0.25 µg/g, i.p. during 21 days) mice and HK activity was assayed. Glucose phosphorylation was increased in the particulate fraction in soleus (312.4% ± 67.1, n = 10), gastrocnemius (369.2% ± 112.4, n = 10) and heart (142.2% ± 13.6, n = 10) muscle in the hyperthyroid group compared to the control group. Hexokinase activity was not affected in brain or liver. No relevant changes were observed in HK activity in the soluble fraction for all tissues investigated. Acute T3 administration (single dose of T3, 1.25 µg/g, i.p.) did not modulate HK activity. Interestingly, HK mRNA levels remained unchanged and HK bound to mitochondria was increased by T3 treatment, suggesting a posttranscriptional mechanism. Analysis of the AKT pathway showed a 2.5-fold increase in AKT and GSK3B phosphorylation in the gastrocnemius muscle in the hyperthyroid group compared to the euthyroid group. Taken together, we show for the first time that THs modulate HK activity specifically in particulate fractions and that this action seems to be under the control of the AKT and GSK3B pathways.

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Section: Discussionmentioning

confidence: 75%

Thyroid states regulate subcellular glucose phosphorylation activity in male mice

Peçanha

Santos

da‐Silva

2017

Endocrine Connections

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“…Further, in a clinical experience involving pharmacologic induction of the euthyroid hypothyroxinemic state in advanced cancer patients, maintenance of normal circulating T 3 levels and euthyroidism—with substantial reduction in circulating levels of T 4 —has been associated with stabilization of the tumor or reduction in tumor size [ 23 ]. On the other hand, differentiated and undifferentiated PC12 (pheochromocytoma) cells distinguish between T 4 and T 3 at αvβ3 [ 24 ], consistent with the existence of subspecialized hormone-binding domains of the receptor on the integrin [ 25 ].…”

Section: Introductionmentioning

confidence: 90%

Thyroid hormone and anti-apoptosis in tumor cells

et al. 2015

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The principal secretory product of the thyroid gland, L-thyroxine (T4), is anti-apoptotic at physiological concentrations in a number of cancer cell lines. Among the mechanisms of anti-apoptosis activated by the hormone are interference with the Ser-15 phosphorylation (activation) of p53 and with TNFα/Fas-induced apoptosis. The hormone also decreases cellular abundance and activation of proteolytic caspases and of BAX and causes increased expression of X-linked inhibitor of apoptosis (XIAP). The anti-apoptotic effects of thyroid hormone largely are initiated at a cell surface thyroid hormone receptor on the extracellular domain of integrin αvβ3 that is amply expressed and activated in cancer cells. Tetraiodothyroacetic acid (tetrac) is a T4 derivative that, in a model of resveratrol-induced p53-dependent apoptosis in glioma cells, blocks the anti-apoptotic action of thyroid hormone, permitting specific serine phosphorylation of p53 and apoptosis to proceed. In a nanoparticulate formulation limiting its action to αvβ3, tetrac modulates integrin-dependent effects on gene expression in human cancer cell lines that include increased expression of a panel of pro-apoptotic genes and decreased transcription of defensive anti-apoptotic XIAP and MCL1 genes. By a variety of mechanisms, thyroid hormone (T4) is an endogenous anti-apoptotic factor that may oppose chemotherapy-induced apoptosis in αvβ3-expressing cancer cells. It is possible to decrease this anti-apoptotic activity pharmacologically by reducing circulating levels of T4 or by blocking effects of T4 that are initiated at αvβ3.

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“…A recent study found that the Erk1/2 signaling pathway modulated the cytoskeleton dynamics of astrocytes in a scratch-wound model (17). Fisetin has been shown to play an important role in regulating the PI3K/Akt and Erk pathways (14,16,36). In the present study, fisetin downregulated the Akt and Erk phosphorylation levels in astrocytes in a dose-dependent manner, but had no effect on p38 expression and phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

Fisetin regulates astrocyte migration and proliferation in vitro

Wang

Yao

et al. 2017

International Journal of Molecular Medicine

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Fisetin (3,3′,4′,7-tetrahydroxyflavone) is a plant flavonol found in fruits and vegetables that has been reported to inhibit migration and proliferation in several types of cancer. Reactive astrogliosis involves astrocyte migration and proliferation, and contributes to the formation of glial scars in central nervous system (CNS) disorders. However, the effect of fisetin on the migration and proliferation of astrocytes remains unclear. In this study, we found that fisetin inhibited astrocyte migration in a scratch-wound assay and diminished the phosphorylation of focal adhesion kinase (FAK; Tyr576/577 and paxillin (Tyr118). It also suppressed cell proliferation, as indicated by the decreased number of 5-ethynyl-2′-deoxyuridine (EdU)-positive cells, induced cell cycle arrest in the G1 phase, reduced the percentage of cells in the G2 and S phase (as measured by flow cytometry), and decreased cyclin D1 expression, but had no effect on apoptosis. Fisetin also decreased the phosphorylation levels of Akt and extracellular signal-regulated kinase (Erk)1/2, but had no effect on the phosphorylation of p38 mitogen-activated protein kinase (MAPK). These results indicate that fisetin inhibits aggressive cell phenotypes by suppressing cell migration and proliferation via the Akt/Erk signaling pathway. Fisetin may thus have potential for use as a therapeutic strategy targeting reactive astrocytes, which may lead to the inhibition of glial scar formation in vitro.

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Thyroid hormones differentially regulate phosphorylation of ERK and Akt via integrin αvβ3 receptor in undifferentiated and differentiated PC‐12 cells

Cited by 17 publications

References 22 publications

Thyroid states regulate subcellular glucose phosphorylation activity in male mice

Thyroid states regulate subcellular glucose phosphorylation activity in male mice

Thyroid hormone and anti-apoptosis in tumor cells

Fisetin regulates astrocyte migration and proliferation in vitro

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