| 1. |
- Augsten, Martin, et al.
(författare)
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Cancer-Associated Fibroblasts Expressing CXCL14 Rely upon NOS1-Derived Nitric Oxide Signaling for Their Tumor-Supporting Properties
- 2014
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Ingår i: Cancer Research. - 1538-7445. ; 74:11, s. 2999-3010
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Tidskriftsartikel (refereegranskat)abstract
- Cancer-associated fibroblasts (CAF) stimulate tumor growth and metastasis. Signals supporting CAF function are thus emerging as candidate therapeutic targets in the tumor microenvironment. The chemokine CXCL14 is a potent inducer of CAF protumorigenic functions. This study is aimed at learning how the protumoral functions of CXCL14-expressing CAF are maintained. We found that the nitric oxide synthase NOS1 is upregulated in CXCL14-expressing CAF and in fibroblasts stimulated with CXCL14. Induction of Nos1 was associated with oxidative stress and occurred together with activation of NRF2 and HIF1 alpha signaling in CXCL14-expressing CAF. Genetic or pharmacologic inhibition of NOS1 reduced the growth of CXCL14-expressing fibroblasts along with their ability to promote tumor formation following coinjection with prostate or breast cancer cells. Tumor analysis revealed reduced macrophage infiltration, with NOS1 downregulation in CXCL14-expressing CAF and lymphangiogenesis as a novel component of CXCL14-promoted tumor growth. Collectively, our findings defined key components of a signaling network that maintains the protumoral functions of CXCL14-stimulated CAF, and they identified NOS1 as intervention target for CAF-directed cancer therapy. (C) 2014 AACR.
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| 2. |
- Frijhoff, Jeroen
(författare)
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Protein tyrosine phosphatases : taking a 'redoxionist' look at PDGFR signaling
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Protein Tyrosine Phosphatases (PTPs) are oxidized and inactivated by reactive oxygen species (ROS) upon stimulation of a wide range of cell surface receptors, including the platelet-derived growth factor (PDGF) receptor (PDGF R). Signaling via this receptor tyrosine kinase stimulates cell proliferation and migration, and it is associated with cancer and cardiovascular diseases. The general aim of this thesis was to achieve a better understanding of the redox regulation of PTPs in PDGFR signaling. Paper I. We analyzed the involvement of mitochondrial ROS in PTP oxidation and PDGFR signaling. We found that depletion of p66Shc, an enzyme that produces hydrogen peroxide from mitochondria, decreased PDGF-induced PDGF R phosphorylation, oxidation of PTP1B, SHP2 and DEP1, and downstream activation of Akt, Erk, PLCy-1 and FAK. Consistently we find that cells that lack p665hc have a decreased migratory response to PDGF. Downregulation of p66Shc in breast cancer cells also led to a decrease in EGF-induced EGFR phosphorylation and downstream signaling. Finally, we could show that downregulation of the mitochondrial hydrogen peroxide scavenger Peroxiredoxin 3 increased PDGFR phosphorylation. We therefore conclude that p66Shc and mitochondrial ROS contribute to PTP oxidation and growth factor signaling. Paper II. Restenosis is a disease in which injury-induced proliferation and migration of vascular smooth muscle cells (VSMCs) leads to vessel wall thickening, which is partially dependent on PDGF signaling. We sought to investigate whether the in vitro findings from paper I have in vivo relevance for restenosis. We show that PDGF activates p66Shc also in VSMCs, and coincides with downstream signaling in a time dependent manner. Downregulation of p66Shc decreased PDGF-induced PDGF R phosphorylation in VSMCs, as well as PLCy-1 phosphorylation and chemotaxis. An in vivo mouse model of restenosis showed that p66Shc knockout (KO) mice displayed decreased restenotic incidence and injury. We conclude that p66Shc contributes to PDGF signaling in VSMCs and restenosis in mice. Paper III. In this paper we studied the potential role of Thioredoxin Reductase 1 (TrxR1) on the reactivation of oxidized PTPs and PDGFR signaling. Cells that lack Thioredoxin Reductase 1 (txnrdt1-), and therefore have an impaired function of the thioredoxin (Trx) system, showed an increased oxidation of PTP1B, whereas the oxidation state of SHP2 was unchanged. Accordingly, in vitro studies showed that the Trx system, with either Trx1 or Trx-related protein 14 (TRP14), was capable of reducing oxidized PTP1B, but not SHP2. Txnrdt-1-cells also showed increased PDGF induced PDGFR phosphorylation at the PTP1B-targeted tyrosine-579/581 residue and increased proliferation. Moreover, deletion of PTP1B inhibited the increase in phosphorylation at tyrosine-579/581 after chemical inhibition of the Trx system compared to PTP1B-reconstituted cells. We conclude that the Trx system impacts on PDGFR signaling through reactivation of oxidized PTP1B. The findings of these studies have uncovered novel regulatory aspects of PTP oxidation in PDGFR signaling that might have an impact on PDGF R-regulated diseases.
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| 3. |
- Shen, Xianli, et al.
(författare)
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Glioma-induced inhibition of caspase-3 in microglia promotes a tumor-supportive phenotype
- 2016
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Ingår i: Nature Immunology. - : Springer Science and Business Media LLC. - 1529-2908 .- 1529-2916. ; 17:11, s. 1282-1290
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Tidskriftsartikel (refereegranskat)abstract
- Glioma cells recruit and exploit microglia (the resident immune cells of the brain) for their proliferation and invasion ability. The underlying molecular mechanism used by glioma cells to transform microglia into a tumor-supporting phenotype has remained elusive. We found that glioma-induced microglia conversion was coupled to a reduction in the basal activity of microglial caspase-3 and increased S-nitrosylation of mitochondria-associated caspase-3 through inhibition of thioredoxin-2 activity, and that inhibition of caspase-3 regulated microglial tumor-supporting function. Furthermore, we identified the activity of nitric oxide synthase 2 (NOS2, also known as iNOS) originating from the glioma cells as a driving stimulus in the control of microglial caspase-3 activity. Repression of glioma NOS2 expression in vivo led to a reduction in both microglia recruitment and tumor expansion, whereas depletion of microglial caspase-3 gene promoted tumor growth. Our results provide evidence that inhibition of the denitrosylation of S-nitrosylated procaspase-3 mediated by the redox protein Trx2 is a part of the microglial pro-tumoral activation pathway initiated by glioma cancer cells.
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