SRC Signaling Is Crucial in the Growth of Synovial Sarcoma Cells

Michels, Sebastian; Trautmann, Marcel; Sievers, Elisabeth; Kindler, Dagmar; Huss, Sebastian; Renner, Marcus; Friedrichs, Nicolaus; Kirfel, Jutta; Steiner, Susanne; Endl, Elmar; Wurst, Peter; Heukamp, Lukas C.; Penzel, Roland; Larsson, Olle; Kawai, Akira; Tanaka, Shinya; Shinmoto, Hiroshi; Schirmacher, Peter; Mechtersheimer, Gunhild; Wardelmann, Eva; Büttner, Reinhard; Hartmann, Wolfgang

doi:10.1158/0008-5472.can-12-3023

Cited by 61 publications

(54 citation statements)

References 39 publications

(56 reference statements)

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“…Primary cathepsin B antibody was obtained from D. J. Buttle, University of Sheffield, UK (Buttle et al, 1988). Antibodies against the following proteins were purchased from manufacturers as listed below: actin (Sigma-Aldrich, St. Louis, MO) (Zhou et al, 2005), calnexin (Millipore, Carrigtwohill, Ireland) (Methner and Mayfield, 2010), EGF receptor (Cell Signaling Technologies, Danvers, MA) (Kawahara et al, 2010), Grb-2 (Cell Signaling Technologies) (Benitez et al, 2011), IGF-1R (Cell Signaling) (Michels et al, 2013), IRS-2 (Cell Signaling) (Gao et al, 2014), Lamp-1 (Cell Signaling), LC-3B (Cell Signaling) (Tong et al, 2012), MAPK (Cell Signaling) (Michels et al, 2013), Akt (Cell Signaling), p-IGF-1Rb (Cell Signaling), p-MAPK (Cell Signaling), p-Akt (Cell Signaling) (Michels et al, 2013), p-Shc A (Cell Signaling) (Krall et al, 2011), RAS (Cell Signaling), Shc A (Cell Signaling), N-Shc (BD Biosciences, San Jose, CA) (Tarr et al, 2002). The secondary goat fluor-568 anti-rabbit antibody was from Invitrogen.…”

Section: Methodsmentioning

confidence: 99%

Cathepsin Inhibition Prevents Autophagic Protein Turnover and Downregulates Insulin Growth Factor-1 Receptor-Mediated Signaling in Neuroblastoma

Soori

Mason

2015

Journal of Pharmacology and Experimental Therapeutics

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Inhibition of the major lysosomal proteases, cathepsins B, D, and L, impairs growth of several cell types but leads to apoptosis in neuroblastoma. The goal of this study was to examine the mechanisms by which enzyme inhibition could cause cell death. Cathepsin inhibition caused cellular accumulation of fragments of the insulin growth factor 1 (IGF-1) receptor. The fragments were located in dense organelles that were characterized as autophagosomes. This novel discovery provides the first clear link between lysosomal function, autophagy, and IGF-1-mediated cell proliferation. A more in-depth analysis of the IGF1 signaling pathway revealed that the mitogen-activated protein kinase (MAPK) cell-proliferation pathway was impaired in inhibitor treated cells, whereas the Akt cell survival pathway remained functional. Shc, an adapter protein that transmits IGF-1 signaling through the MAPK pathway, was sequestered in autophagosomes; whereas IRS-2, an adapter protein that transmits IGF-1 signaling through the Akt pathway, was unaffected by cathepsin inhibition. Furthermore, Shc was sequestered in autophagosomes as its active form, indicating that autophagy is a key mechanism for downregulating IGF-1-induced cell proliferation. Cathepsin inhibition had a greater effect on autophagic sequestration of the neuronal specific adapter protein, Shc-C, than ubiquitously expressed Shc-A, providing mechanistic support for the enhanced sensitivity of neuronally derived tumor cells. We also observed impaired activation of MAPK by epidermal growth factor treatment in inhibitor-treated cells. The Shc adapter proteins are central to transducing proliferation signaling by a range of receptor tyrosine kinases; consequently, cathepsin inhibition may become an important therapeutic approach for treating neuroblastoma and other tumors of neuronal origin.

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Section: Methodsmentioning

confidence: 99%

Cathepsin Inhibition Prevents Autophagic Protein Turnover and Downregulates Insulin Growth Factor-1 Receptor-Mediated Signaling in Neuroblastoma

Soori

Mason

2015

Journal of Pharmacology and Experimental Therapeutics

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“…5F). Since DCA treatment did not decrease Src phosphorylation at Tyr 416 below baseline, we sought to better understand the interaction between DCA and Src by investigating phosphorylation at Tyr 527 , the inhibitory Src phosphorylation site (49). We found that DCA treatment stimulated Src Tyr 527 phosphorylation, which was maximized at 2 h (Fig.…”

Section: Dca-induced Inhibition Of Cell Proliferation Is Mediated By mentioning

confidence: 95%

Bile acids regulate intestinal cell proliferation by modulating EGFR and FXR signaling

Dossa

Escobar

Golden

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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Bile acids (BAs) are synthesized in the liver and secreted into the intestine. In the lumen, enteric bacteria metabolize BAs from conjugated, primary forms into more toxic unconjugated, secondary metabolites. Secondary BAs can be injurious to the intestine and may contribute to disease. The epidermal growth factor receptor (EGFR) and the nuclear farnesoid X receptor (FXR) are known to interact with BAs. In this study we examined the effects of BAs on intestinal epithelial cell proliferation and investigated the possible roles for EGFR and FXR in these effects. We report that taurine-conjugated cholic acid (TCA) induced proliferation, while its unconjugated secondary counterpart deoxycholic acid (DCA) inhibited proliferation. TCA stimulated phosphorylation of Src, EGFR, and ERK 1/2. Pharmacological blockade of any of these pathways or genetic ablation of EGFR abrogated TCA-stimulated proliferation. Interestingly, Src or EGFR inhibitors eliminated TCA-induced phosphorylation of both molecules, suggesting that their activation is interdependent. In contrast to TCA, DCA exposure diminished EGFR phosphorylation, and pharmacological or siRNA blockade of FXR abolished DCA-induced inhibition of proliferation. Taken together, these results suggest that TCA induces intestinal cell proliferation via Src, EGFR, and ERK activation. In contrast, DCA inhibits proliferation via an FXR-dependent mechanism that may include downstream inactivation of the EGFR/Src/ERK pathway. Since elevated secondary BA levels are the result of specific bacterial modification, this may provide a mechanism through which an altered microbiota contributes to normal or abnormal intestinal epithelial cell proliferation.

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“…With the use of immunohistochemistry and Western blotting, the total Src and phosphorylated Src (Y419) were found to be activated in human sarcoma tissues (leiomyosarcoma, high-grade osteosarcoma and liposarcoma) and sarcoma cell lines (osteosarcoma, Ewing's sarcoma, leiomyosarcoma and rhabdomyosarcoma) (45). Furthermore, Src was identified as one of the most strongly phosphorylated kinases in synovial sarcoma cells (46). Src activity was demonstrated to be upregulated in anoikis-resistant human osteosarcoma cells, SAOS-2, compared with their parental population (47).…”

Section: Function Of Src In Sarcomamentioning

confidence: 99%

The importance of Src signaling in sarcoma

et al. 2015

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Abstract. Src is a tyrosine kinase that is of significance in tumor biology. The present review focuses on Src, its molecular structure, and role in cancer, in addition to its expression and function in sarcoma. In addition, the feasibility of Src as a potential drug target for the treatment of sarcoma is also discussed. Previous studies have suggested that Src has essential functions in cell proliferation, apoptosis, invasion, metastasis and the tumor microenvironment. Thus, it may be a potential target for cancer therapy. Src has been found to enhance proliferation, reduce apoptosis and promote metastasis in certain subtypes of sarcoma, including osteosarcoma, chondrosarcoma and Ewing's sarcoma. Furthermore, a number of novel effective therapeutic agents, such as SI-83, which target Src have been investigated in vitro and in vivo. Bosutinib and dasatinib, which inhibit Src, have been approved by the U.S. Food and Drug Administration for the treatment of chronic myelogenous leukemia. In addition, vandetanib is approved for the treatment of medullary thyroid cancer. Furthermore, the Src inhibitor, saracatinib, is currently in clinical trials for the treatment of a variety of solid tumors, including breast and lung cancers. Thus, Src is considered to be an important factor in sarcoma progression and may present a novel clinical therapeutic target. This review demonstrates the importance and clinical relevance of Src in sarcoma, and discusses a number of small molecular inhibitors of src kinase, such as dasatinib and sarcatinib, which are currently in clinical trials for the treatment of sarcoma patients.

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SRC Signaling Is Crucial in the Growth of Synovial Sarcoma Cells

Cited by 61 publications

References 39 publications

Cathepsin Inhibition Prevents Autophagic Protein Turnover and Downregulates Insulin Growth Factor-1 Receptor-Mediated Signaling in Neuroblastoma

Cathepsin Inhibition Prevents Autophagic Protein Turnover and Downregulates Insulin Growth Factor-1 Receptor-Mediated Signaling in Neuroblastoma

Bile acids regulate intestinal cell proliferation by modulating EGFR and FXR signaling

The importance of Src signaling in sarcoma

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