Role of the Transforming Growth Factor-β in regulating hepatocellular carcinoma oxidative metabolism

Soukupová, Jitka; Malfettone, Andrea; Hyroššová, Petra; Hernández‐Álvarez, María Isabel; Peñuelas‐Haro, Irene; Bertrán, Esther; Junza, Alexandra; Capellades, Jordi; Giannelli, Gianluigi; Yanes, Óscar; Zorzano, António; Perales, José C.; Fabregat, Isabel

doi:10.1038/s41598-017-12837-y

Cited by 59 publications

(63 citation statements)

References 31 publications

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“…As discussed, NK cells treated with TGFβ have reduced levels of oxphos and maximal respiration (47). This has also been shown in hepatocellular carcinoma cells, where TGFβ treatment skewed metabolism away from oxphos in order to promote the epithelial/mesenchymal cell transition (85). Interestingly, the expression of SLC7A5 was increased on the cancer cells in response to TGFβ.…”

Section: Tgfβ and Mitochondrial Structure And Functionmentioning

confidence: 56%

NK Cell Metabolism and TGFβ – Implications for Immunotherapy

Slattery

Gardiner

2019

Front. Immunol.

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NK cells are innate lymphocytes which play an essential role in protection against cancer and viral infection. Their functions are dictated by many factors including the receptors they express, cytokines they respond to and changes in the external environment. These cell processes are regulated within NK cells at many levels including genetic, epigenetic and expression (RNA and protein) levels. The last decade has revealed cellular metabolism as another level of immune regulation. Specific immune cells adopt metabolic configurations that support their functions, and this is a dynamic process with cells undergoing metabolic reprogramming during the course of an immune response. Upon activation with pro-inflammatory cytokines, NK cells upregulate both glycolysis and oxphos metabolic pathways and this supports their anti-cancer functions. Perturbation of these pathways inhibits NK cell effector functions. Anti-inflammatory cytokines such as TGFβ can inhibit metabolic changes and reduce functional outputs. Although a lot remains to be learned, our knowledge of potential molecular mechanisms involved is growing quickly. This review will discuss our current knowledge on the role of TGFβ in regulating NK cell metabolism and will draw on a wider knowledge base regarding TGFβ regulation of cellular metabolic pathways, in order to highlight potential ways in which TGFβ might be targeted to contribute to the exciting progress that is being made in terms of adoptive NK cell therapies for cancer.

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Section: Tgfβ and Mitochondrial Structure And Functionmentioning

confidence: 56%

NK Cell Metabolism and TGFβ – Implications for Immunotherapy

Slattery

Gardiner

2019

Front. Immunol.

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“…An important role in the metabolic reprogramming of cancer cells is played by the TGF-β1 (Transforming growth factor beta 1) through the upregulation of Smad, p38 MAPK and PI3K/AKT pathways [ 73 ]. Specifically, TGF-β1 promotes tumor progression by inducing a switch from an epithelial to a mesenchymal/migratory phenotype in HCC cells, reducing mitochondrial respiration and enhancing glutamine transporter SLC7A5b (Solute Carrier Family 7 Member 5), glutaminase 1, and pentose phosphate cycle [ 74 ]. The latter provides precursors for nucleotide synthesis and prevents oxidative stress and redox homeostasis.…”

Section: The Genes Involvedmentioning

confidence: 99%

“…The latter provides precursors for nucleotide synthesis and prevents oxidative stress and redox homeostasis. Furthermore, TGF-β1 and its mediated signaling pathway induces HIF1α to participate in the process of metabolic reprogramming under normoxic conditions [ 74 ].…”

Section: The Genes Involvedmentioning

confidence: 99%

The Warburg Effect 97 Years after Its Discovery

Pascale

Calvisi

Simile

et al. 2020

Cancers

174

128

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The deregulation of the oxidative metabolism in cancer, as shown by the increased aerobic glycolysis and impaired oxidative phosphorylation (Warburg effect), is coordinated by genetic changes leading to the activation of oncogenes and the loss of oncosuppressor genes. The understanding of the metabolic deregulation of cancer cells is necessary to prevent and cure cancer. In this review, we illustrate and comment the principal metabolic and molecular variations of cancer cells, involved in their anomalous behavior, that include modifications of oxidative metabolism, the activation of oncogenes that promote glycolysis and a decrease of oxygen consumption in cancer cells, the genetic susceptibility to cancer, the molecular correlations involved in the metabolic deregulation in cancer, the defective cancer mitochondria, the relationships between the Warburg effect and tumor therapy, and recent studies that reevaluate the Warburg effect. Taken together, these observations indicate that the Warburg effect is an epiphenomenon of the transformation process essential for the development of malignancy.

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“…A common mediator of profibrotic responses is the transcriptional comodulators YAP and TAZ. 42 In that YAP/TAZ has been shown to regulate metabolic activity 43 as well as many aspects of the fibroblast response to TGFβ, [44][45][46] we next addressed whether YAP/TAZ might be a mediator of PD-L1 1) and murine (AKR-2B and Swiss 3T3) fibroblast cell lines were stimulated with 5 ng/mL TGFβ (+) or Vehicle (−; 4 Mm HCl + 0.1% BSA) for 18 hours and Western blotted for PD-L1 or GAPDH. B, (Top) MRC5 and AKR-2B cells were stimulated with Vehicle (−) or TGFβ (+) and assessed for PD-L1, collagen 1 (COL1α1), and pSmad3 protein at the indicated times.…”

Section: Yap/taz Regulates Pd-l1 Expression By Tgfβmentioning

confidence: 99%

Transforming growth factor beta induces fibroblasts to express and release the immunomodulatory protein PD‐L1 into extracellular vesicles

et al. 2019

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Transforming growth factor-beta (TGFβ) is an enigmatic protein with various roles in healthy tissue homeostasis/development as well as the development or progression of cancer, wound healing, fibrotic disorders, and immune modulation, to name a few. As TGFβ is causal to various fibroproliferative disorders featuring localized or systemic tissue/organ fibrosis as well as the activated stroma observed in various malignancies, characterizing the pathways and players mediating its action is fundamental. In the current study, we found that TGFβ induces the expression of the immunoinhibitory molecule Programed death-ligand 1 (PD-L1) in human and murine fibroblasts in a Smad2/3-and YAP/TAZ-dependent manner. Furthermore, PD-L1 knockdown decreased the TGFβ-dependent induction of extracellular matrix proteins, including collagen Iα1 (colIα1) and alpha-smooth muscle actin (α-SMA), and cell migration/wound healing. In addition to an endogenous role for PD-L1 in profibrotic TGFβ signaling, TGFβ stimulated-human lung fibroblast-derived PD-L1 into extracellular vesicles (EVs) capable of inhibiting T cell proliferation in response to T cell receptor stimulation and mediating fibroblast cell migration. These findings provide new insights and potential targets for a variety of fibrotic and malignant diseases. K E Y W O R D Sfibroblast, checkpoint inhibitor, extracellular vesicles, signaling 2214 | KANG et Al. | 2223 KANG et Al. F I G U R E 6EVs from TGFβ treated fibroblasts inhibit T cell proliferation and cell migration. A, MRC5 cultures were treated in the absence(−) or presence (+) of TGFβ (10 ng/mL) for 3 days. Following the collection of the supernatant for EV isolation, the cells were lysed, and both were assessed for expression of PD-L1 or the EV-associated protein CD63 by Western blotting (representative of 3 independent experiments). B, EV particle size distribution was identified through nanoparticle tracking analysis and processed with NTA software (NanoSight). C, EVs were purified from MRC5 cells cultured in the absence (−) or presence (+) of TGFβ as in (A). Peripheral blood mononuclear cells (n = 5 volunteers) were then treated with anti-CD3 (+αCD3; 500 ng/mL) to activate T cell proliferation and incubated for 6 days with no EVs, EVs (10 μg/mL) isolated from cells ± TGFβ, or EVs isolated from cells ± TGFβ ± blocking antibody to PD-L1 (10 μg/mL Avelumab). The percent change in proliferation, measured by carboxyfluorescein diacetate succinimidyl ester (CFSE) content, compared to anti-CD3 treatment alone is shown. D, (Top 2 panels) Transwell invasion assays were performed in MRC5 cells treated in 0.1% FBS/DME alone (Con) or supplemented with 5 ng/mL TGFβ for 18 hours as described in Materials and Methods. (Bottom 3 panels) MRC5 cells were assessed as in the top panels except that the 0.1% FBS/DME contained EVs (10 μg/mL) isolated from MRC5 cells ± TGFβ or MRC5 cells which had been treated with siRNA to PD-L1 and then stimulated with TGFβ. E, Quantitation of transwell migration of cells treated in (D). Data reflect mean ±...

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Role of the Transforming Growth Factor-β in regulating hepatocellular carcinoma oxidative metabolism

Cited by 59 publications

References 31 publications

NK Cell Metabolism and TGFβ – Implications for Immunotherapy

NK Cell Metabolism and TGFβ – Implications for Immunotherapy

The Warburg Effect 97 Years after Its Discovery

Transforming growth factor beta induces fibroblasts to express and release the immunomodulatory protein PD‐L1 into extracellular vesicles

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