Comparative effects of transforming growth factor beta isoforms on redox metabolism in thyroid cells

Oglio, Romina; Thomasz, Lisa; Salvarredi, Leonardo; Juvenal, Guillermo; Pisarev, Mario A.

doi:10.1016/j.mce.2017.10.011

Cited by 6 publications

(6 citation statements)

References 53 publications

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“…In our in vitro models of pancreatic cancer, the cytokine was cytotoxic at the highest doses of 10 ng/mL and especially after prolonged exposure, due to the strong stimulation of respiratory chain associated with the overproduction of ROS, which in turn damaged mitochondrial membrane potential. It is of note that these concentrations are normally used in in vitro studies exploring EMT [34][35][36]. Our observation that the high concentration of TGFβ affects viability on long-term treatments is not in contrast with data from other studies, because the most common experimental setup in EMT investigation is the treatment with 10 ng/mL TGFβ only for short EMT induction (up to 48 h in pancreatic cancer [46][47][48]), with a lower concentration for longer induction (for example, breast cancer [49][50][51][52] and melanoma cancer [53]).…”

Section: Discussionmentioning

confidence: 99%

“…Given the toxicity of TGFβ treatment at high doses, we sought to investigate the cellular process mainly involved. In this regard, it has been widely demonstrated that toxicity is related to an excessive ROS production [9]; indeed, the production of ROS triggered by TGFβ is well known and it occurs through many mechanisms, such as the impairment of the mitochondrial function and the suppression of antioxidant enzymes [36]. Considering the above, we measured the production of ROS in PANC-1 and CAPAN-2 cells under acute (10 ng/mL for 24 h) and prolonged (2 ng/mL for 8 days) TGFβ treatment.…”

Section: The Cytotoxic Production Of Ros Triggered By Tgfβ Is Abated At Low Concentration Of the Cytokinementioning

confidence: 99%

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TGF Beta Induces Vitamin D Receptor and Modulates Mitochondrial Activity of Human Pancreatic Cancer Cells

Fiz

Apprato

Ricca

et al. 2021

Cancers

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The inflammatory cytokine TGFβ is both a tumor suppressor during cancer initiation and a promoter of metastasis along cancer progression. Inflammation and cancer are strictly linked, and cancer onset often correlates with the insufficiency of vitamin D, known for its anti-inflammatory properties. In this study, we investigated the interplay between TGFβ and vitamin D in two models of human pancreatic cancer, and we analyzed the metabolic effects of a prolonged TGFβ treatment mimicking the inflammatory environment of pancreatic cancer in vivo. We confirmed the induction of the vitamin D receptor previously described in epithelial cells, but the inhibitory effects of vitamin D on epithelial–mesenchymal transition (EMT) were lost when the hormone was given after a long treatment with TGFβ. Moreover, we detected an ROS-mediated toxicity of the acute treatment with TGFβ, whereas a chronic exposure to low doses had a protumorigenic effect. In fact, it boosted the mitochondrial respiration and cancer cell migration without ROS production and cytotoxicity. Our observations shed some light on the multifaceted role of TGFβ in tumor progression, revealing that a sustained exposure to TGFβ at low doses results in an irreversibly increased EMT associated with a metabolic modulation which favors the formation of metastasis.

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Section: Discussionmentioning

confidence: 99%

Section: The Cytotoxic Production Of Ros Triggered By Tgfβ Is Abated At Low Concentration Of the Cytokinementioning

confidence: 99%

TGF Beta Induces Vitamin D Receptor and Modulates Mitochondrial Activity of Human Pancreatic Cancer Cells

Fiz

Apprato

Ricca

et al. 2021

Cancers

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“…Recently, it has been shown that ROS generation by NOX4 is a critical mediator of the down regulation of the sodium iodide symporter (NIS) in BRAF V600E mutated thyroid cell lines (Azouzi et al, 2017). Moreover, the knockdown of NOX4 significantly reduced the TGFβ1 effect on cell viability in human thyroid follicular carcinoma cells but not in differentiated rat thyroid cells (Oglio et al, 2018). These results suggest a role of NOX4 depending on the state of thyroid cellular differentiation.…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 94%

“…Since Selenium dependent enzymes are very important for the modulation of thyroid ROS levels, we investigated the effect of Selenium (Se) on glutathione peroxidase (GPx), NOX4, TGFβ1 and some thyroid specific genes expression. The selenite concentrations (0.01-0.1µM) used here were within physiological range (Demelash et al, 2004) with no unwanted cytotoxic effects (Leoni et al, 2016;Oglio et al, 2018). Since TSH is required for GPx expression in FRTL-5 cells (Björkman and Ekholm, 1995;Villette et al, 1998), the following experiments were done with TSH and in the presence or absence of insulin.…”

Section: Selenium Regulated Nox4 Expressionmentioning

confidence: 99%

Participation of NADPH 4 oxidase in thyroid regulation

Oglio

Salvarredi

Rossich

et al. 2019

Molecular and Cellular Endocrinology

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Different factors are involved in thyroid function and proliferation such as thyrotropin (TSH), insulin, growth factors, iodide, etc. TSH and IGF1/insulin increase proliferation rate and stimulate genes involved in thyroid differentiation. In the present study, we analyze the physiological regulation of NOX4 expression by TSH, insulin and iodine, and the role of NOX4 on thyroid genes expression. Differentiated rat thyroid cells (FRTL-5) were incubated in the presence or absence of TSH/ insulin and TTF2, PAX8, TPO, NIS, NOX4, TGFβ1, FOXO1/3 mRNA levels were examined by Real Time PCR. We showed that TSH and insulin repress NOX4 expression and appears to be inversely correlated with some thyroid genes. SiRNA targeted knockdown of NOX4 increased mRNA levels of TGFβ1, TPO, PAX8, TTF2, FOXO1 and FOXO3. A PI3K inhibitor (LY294002), increases the expression of NIS, TTF2 and FOXO1/3, however PI3K/AKT pathway does not regulate NOX4 expression. We observed that iodine increased NOX4 expression and knockdown of NOX4 reduced ROS and reversed the inhibitory effect of iodine on NIS, TPO, PAX8 and TTF2 expression. Our findings provide strong evidence that NOX4 could be a novel signalling modulator of TSH/insulin pathway and would have a critical role in the autoregulatory mechanism induced by iodine.

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“…Contrary to differentiated thyrocytes, undifferentiated cells of thyroid carcinomas are resistant to TGF-β anti-proliferative effects [125]. Data obtained from human thyroid follicular carcinoma cells implicated NOX4 as one of the mediators of this TGF-β resistance as siRNA-mediated silencing of NOX4 countered TGF-β inhibitory effect on cell proliferation [126].…”

Section: Nadph Oxidases In Thyroid Pathologiesmentioning

confidence: 99%

H2O2 Metabolism in Normal Thyroid Cells and in Thyroid Tumorigenesis: Focus on NADPH Oxidases

2019

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Thyroid hormone synthesis requires adequate hydrogen peroxide (H2O2) production that is utilized as an oxidative agent during the synthesis of thyroxin (T4) and triiodothyronine (T3). Thyroid H2O2 is generated by a member of the family of NADPH oxidase enzymes (NOX-es), termed dual oxidase 2 (DUOX2). NOX/DUOX enzymes produce reactive oxygen species (ROS) as their unique enzymatic activity in a timely and spatially regulated manner and therefore, are important regulators of diverse physiological processes. By contrast, dysfunctional NOX/DUOX-derived ROS production is associated with pathological conditions. Inappropriate DUOX2-generated H2O2 production results in thyroid hypofunction in rodent models. Recent studies also indicate that ROS improperly released by NOX4, another member of the NOX family, are involved in thyroid carcinogenesis. This review focuses on the current knowledge concerning the redox regulation of thyroid hormonogenesis and cancer development with a specific emphasis on the NOX and DUOX enzymes in these processes.

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Comparative effects of transforming growth factor beta isoforms on redox metabolism in thyroid cells

Cited by 6 publications

References 53 publications

TGF Beta Induces Vitamin D Receptor and Modulates Mitochondrial Activity of Human Pancreatic Cancer Cells

TGF Beta Induces Vitamin D Receptor and Modulates Mitochondrial Activity of Human Pancreatic Cancer Cells

Participation of NADPH 4 oxidase in thyroid regulation

H2O2 Metabolism in Normal Thyroid Cells and in Thyroid Tumorigenesis: Focus on NADPH Oxidases

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