Isoform-Specific Activation of Latent Transforming Growth Factor β (LTGF-β) by Reactive Oxygen Species

Jobling, Michael F.; Mott, Joni D.; Finnegan, Monica T.; Jurukovski, Vladimir; Erickson, Anna C.; Walian, Peter J.; Taylor, Scott; Ledbetter, Steven; Lawrence, Catherine M.; Rifkin, Daniel B.; Barcellos‐Hoff, Mary Helen

doi:10.1667/rr0695.1

Cited by 253 publications

(183 citation statements)

References 92 publications

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“…Interestingly, TGFβ1‐mediated fibroblast activation requires both intra‐ and extracellular ROS as membrane‐permeable or ‐impermeable forms of antioxidant enzymes abrogate the induction of different sets of CAF markers by TGFβ1 (not shown). Such extracellular functions of ROS have been described previously, for example, TGFβ‐induced ROS activate latent TGFβ and cross‐link fibroblast‐derived ECM proteins 36, 37. Further studies are underway to identify the direct oxidative targets of Nox4‐derived ROS during TGFβ1‐mediated fibroblast activation.…”

Section: Discussionmentioning

confidence: 53%

Inhibition of Nox4‐dependent ROS signaling attenuates prostate fibroblast activation and abrogates stromal‐mediated protumorigenic interactions

Sampson

Brunner

Weber

et al. 2018

Intl Journal of Cancer

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Carcinoma‐associated fibroblasts (CAFs) play a key onco‐supportive role during prostate cancer (PCa) development and progression. We previously reported that the reactive oxygen species (ROS)‐producing enzyme NADPH oxidase 4 (Nox4) is essential for TGFβ1‐mediated activation of primary prostate human fibroblasts to a CAF‐like phenotype. This study aimed to further investigate the functional relevance of prostatic Nox4 and determine whether pharmacological inhibition of stromal Nox4 abrogates paracrine‐mediated PCa‐relevant processes. RNA in situ hybridization revealed significantly elevated Nox4 mRNA levels predominantly in the peri‐tumoral stroma of clinical PCa with intense stromal Nox4 staining adjacent to tumor foci expressing abundant TGFβ protein levels. At pharmacologically relevant concentrations, the Nox1/Nox4 inhibitor GKT137831 attenuated ROS production, CAF‐associated marker expression and migration of TGFβ1‐activated but not nonactivated primary human prostate fibroblasts. Similar effects were obtained upon shRNA‐mediated silencing of Nox4 but not Nox1 indicating that GKT137831 primarily abrogates TGFβ1‐driven fibroblast activation via Nox4 inhibition. Moreover, inhibiting stromal Nox4 abrogated the enhanced proliferation and migration of PCa cell lines induced by TGFβ1‐activated prostate fibroblast conditioned media. These effects were not restricted to recombinant TGFβ1 as conditioned media from PCa cell lines endogenously secreting high TGFβ1 levels induced fibroblast activation in a stromal Nox4‐ and TGFβ receptor‐dependent manner. Importantly, GKT137831 also attenuated PCa cell‐driven fibroblast activation. Collectively, these findings suggest the TGFβ‐Nox4 signaling axis is a key interface to dysregulated reciprocal stromal–epithelial interactions in PCa pathophysiology and provide a strong rationale for further investigating the applicability of Nox4 inhibition as a stromal‐targeted approach to complement current PCa treatment modalities.

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Section: Discussionmentioning

confidence: 53%

Inhibition of Nox4‐dependent ROS signaling attenuates prostate fibroblast activation and abrogates stromal‐mediated protumorigenic interactions

Sampson

Brunner

Weber

et al. 2018

Intl Journal of Cancer

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“…The possibility of cold plasma activating TGF-β may involve one or both of two possible mechanisms as follows. The first of these is ROS-based activation, as described previously 34,35 . ROS in this context are generated by cold plasma.…”

Section: Discussionmentioning

confidence: 99%

Cold plasma on full-thickness cutaneous wound accelerates healing through promoting inflammation, re-epithelialization and wound contraction

Nasruddin

Nakajima

Mukai

et al. 2014

Clinical Plasma Medicine

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We investigated cold plasma effects on acute wounds of mice. The mice were classified into experimental and control groups. In the former, wounds were treated using cold plasma once daily for 1 minute, and then covered with hydrocolloid dressing; wounds in the control were left to heal under hydrocolloid dressing. Daily evaluation was conducted for 15 days. General and specific staining was applied to evaluate re-epithelialization, neutrophil, macrophage, myofibroblast and transforming growth factor beta. It was found that cold plasma accelerated wound healing by one day. Plasma may promote the late phase of inflammation, accelerate reepithelialization and increase wound contraction.3

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“…Thrombin, matrix metalloproteinases (MMP)-2 and -9, and thrombospondin-1 (THBS1), which can all be enriched in carcinomas, are each capable of cleaving LAP to activate TGF-b (SchultzCherry et al 1994). Other means of ligand activation include acidic pH, reactive oxygen species (ROS) and ionizing radiation, all of which are relevant to tumor progression and cancer treatment (Barcellos-Hoff 1993;Barcellos-Hoff and Dix 1996;Annes et al 2004;Jobling et al 2006;Shi et al 2011).…”

Section: The Tgf-b Signaling Pathwaymentioning

confidence: 99%

Targeting TGF-β Signaling for Therapeutic Gain

Akhurst

2017

Cold Spring Harb Perspect Biol

174

139

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Transforming growth factor bs (TGF-bs) are closely related ligands that have pleiotropic activity on most cell types of the body. They act through common heterotetrameric TGF-b type II and type I transmembrane dual specificity kinase receptor complexes, and the outcome of signaling is context-dependent. In normal tissue, they serve a role in maintaining homeostasis. In many diseased states, particularly fibrosis and cancer, TGF-b ligands are overexpressed and the outcome of signaling is diverted toward disease progression. There has therefore been a concerted effort to develop drugs that block TGF-b signaling for therapeutic benefit. This review will cover the basics of TGF-b signaling and its biological activities relevant to oncology, present a summary of pharmacological TGF-b blockade strategies, and give an update on preclinical and clinical trials for TGF-b blockade in a variety of solid tumor types.

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Isoform-Specific Activation of Latent Transforming Growth Factor β (LTGF-β) by Reactive Oxygen Species

Cited by 253 publications

References 92 publications

Inhibition of Nox4‐dependent ROS signaling attenuates prostate fibroblast activation and abrogates stromal‐mediated protumorigenic interactions

Inhibition of Nox4‐dependent ROS signaling attenuates prostate fibroblast activation and abrogates stromal‐mediated protumorigenic interactions

Cold plasma on full-thickness cutaneous wound accelerates healing through promoting inflammation, re-epithelialization and wound contraction

Targeting TGF-β Signaling for Therapeutic Gain

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