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Query: EC:6.2.1.1 (ACS)
 78,556 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The chemopreventative effects of dithiolethione compounds are attributed to their activation of antioxidant response elements (AREs) by reacting with the Nrf2/Keap1 protein complex. In this study, we show antiproliferative effects of the dithiolethione compound ACS-1 in human cancer cell lines (A549 and MDA-MB-231) by increasing the activity of the tumor suppressor protein phoshatase 2A (PP2A). ACS-1 inhibited epidermal growth factor (EGF)-induced cellular proliferation in a concentration- and time-dependent manner. Akt activation, as determined by serine-473 phosphorylation, was inhibited by ACS-1 in cells stimulated with either EGF or fibronectin. Furthermore, ACS-1 inhibited mammalian target of rapamycin signaling and decreased c-myc protein levels. ACS-1 did not proximally alter EGF receptor or integrin signaling, but caused a concentration-dependent increase in PP2A activity. The effect of ACS-1 on Akt activation was not observed in the presence of the PP2A inhibitor okadaic acid. ACS-1 effects on PP2A activity were independent of ARE activation and cAMP formation. In addition to ACS-1, other dithiolethione compounds showed similar effects in reducing Akt activation, suggesting that this class of compounds may have other effects beyond chemoprevention.
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PMID:Dithiolethione compounds inhibit Akt signaling in human breast and lung cancer cells by increasing PP2A activity. 1970 Dec 46

Attachment of ligands to the surface of nanoparticles (NPs) is an attractive approach to target specific cells and increase intracellular delivery of nanocargos. To expedite investigation of targeted NPs, we engineered human cancer cells to express chimeric receptors that bind polyethylene glycol (PEG) and internalize stealth NPs in a fashion similar to ligand-targeted liposomes against epidermal growth factor receptor 1 or 2 (HER1 or HER2), which are validated targets for cancer therapy. Measurement of the rate of endocytosis and lysosomal accumulation of small (80-94 nm) or large (180-220 nm) flexible liposomes or more rigid lipid-coated mesoporous silica particles in human HT29 colon cancer and SKBR3 breast cancer cells that express chimeric receptors revealed that larger and more rigid NPs were internalized more slowly than smaller and more flexible NPs. An exception is when both the small and large liposomes underwent endocytosis via HER2. HER1 mediated faster and greater uptake of NPs into cells but retained NPs less well as compared to HER2. Lysosomal accumulation of NPs internalized via HER1 was unaffected by NP rigidity but was inversely related to NP size, whereas large rigid NPs internalized by HER2 displayed increased lysosomal accumulation. Our results provide insight into the effects of NP properties on receptor-mediated endocytosis and suggest that anti-PEG chimeric receptors may help accelerate investigation of targeted stealth NPs.
ACS Nano 2016 Jan 26
PMID:Engineering Chimeric Receptors To Investigate the Size- and Rigidity-Dependent Interaction of PEGylated Nanoparticles with Cells. 2674 Nov 47

Bioluminescence is a useful tool for imaging of cancer in in vivo animal models that endogenously express luciferase, an enzyme that requires a substrate for visual readout. Current bioluminescence imaging, using commonly available luciferin substrates, only lasts a short time (15-20 min). To avoid repeated administration of luciferase substrate during cancer detection and surgery, a long lasting bioluminescence imaging substrate or system is needed. A novel water-soluble biotinylated luciferase probe, B-YL (1), was synthesized. A receptor-targeted complex of B-YL with streptavidin (SA) together with a biotinylated epidermal growth factor short peptide (B-EGF) (SA/B-YL/B-EGF = 1:3:1, molar ratio) was then prepared to demonstrate selective targeting. The complex was incubated with brain cancer cell lines overexpressing the EGF receptor (EGFR) and transfected with the luciferase gene. Results show that the complex specifically detects cancer cells by bioluminescence. The complex was further used to image xenograft brain tumors transfected with a luciferase gene in mice. The complex detects the tumor immediately, and bioluminescence lasts for 5 days. Thus, the complex generates a long lasting bioluminescence for cancer detection in mice. The complex with selective targeting may be used in noninvasive cancer diagnosis and accurate surgery in cancer treatment in clinics in the future.
ACS Chem Neurosci 2018 01 17
PMID:Biotinylated Bioluminescent Probe for Long Lasting Targeted in Vivo Imaging of Xenografted Brain Tumors in Mice. 2853 51

Surface modifications with tethered growth factors have mainly been applied to synthetic polymeric biomaterials in well-controlled, acellular settings, followed by seeding with cells. The known bio-orthogonality of copper-free click chemistry provides an opportunity to not only use it in vitro to create scaffolds or pro-migratory tracks in the presence of living cells, but also potentially apply it to living tissues directly as a coupling modality in situ. In this study, we studied the chemical coupling of growth factors to collagen using biocompatible copper-free click chemistry and its effect on the enhancement of growth factor activity in vitro. We verified the characteristics of modified epidermal growth factor (EGF) using mass spectrometry and an EGF/EGF receptor binding assay, and evaluated the chemical immobilization of EGF on collagen by copper-free click chemistry using surface X-ray photoelectron spectroscopy (XPS), surface plasmon resonance (SPR) spectroscopy, and enzyme-linked immunosorbent assay (ELISA). We found that the anchoring was noncytotoxic, biocompatible, and rapid. Moreover, the surface-immobilized EGF had significant effects on epithelial cell attachment and proliferation. Our results demonstrate the possibility of copper-free click chemistry as a tool for covalent bonding of growth factors to collagen in the presence of living cells. This approach is a novel and potentially clinically useful application of copper-free click chemistry as a way of anchoring growth factors to collagen and foster epithelial wound healing.
ACS Appl Mater Interfaces 2017 Jul 19
PMID:Tethering Growth Factors to Collagen Surfaces Using Copper-Free Click Chemistry: Surface Characterization and in Vitro Biological Response. 2859 94

Cell targeting protein toxins have gained increasing interest for cancer therapy aimed at increasing the therapeutic window and reducing systemic toxicity. Because recombinant expression of immunotoxins consisting of a receptor-binding and a cell-killing moiety is hampered by their high toxicity in a eukaryotic production host, most applications rely on recombinant production of fusion proteins consisting of an antibody fragment and a protein toxin in bacterial hosts such as Escherichia coli ( E. coli). These fusions often lack beneficial properties of whole antibodies like extended serum half-life or efficient endocytic uptake via receptor clustering. Here, we describe the production of full-length antibody immunotoxins using self-splicing split inteins. To this end, the short (11 amino acids) N-terminal intein part of the artificially designed split intein M86, a derivative of the Ssp DnaB intein, was recombinantly fused to the heavy chain of trastuzumab, a human epidermal growth factor receptor 2 (HER2) receptor targeting antibody and to a nanobody-Fc fusion targeting the HER1 receptor, respectively. Both antibodies were produced in Expi293F cells. The longer C-terminal counterpart of the intein was genetically fused to the protein toxins gelonin or Pseudomonas Exotoxin A, respectively, and expressed in E. coli via fusion to maltose binding protein. Using optimized in vitro splicing conditions, we were able to generate a set of specific and potent immunotoxins with IC50 values in the mid- to subpicomolar range.
ACS Chem Biol 2018 08 17
PMID:Generation of Potent Anti-HER1/2 Immunotoxins by Protein Ligation Using Split Inteins. 2992 62

The CXCL12 chemokine receptor CXCR4 belongs to the GPCR superfamily and is often overexpressed in cancer, being involved in tumor progression and metastasis. How CXCR4 signaling integrates with other relevant oncogenic transduction pathways and the role of GPCR regulatory mechanisms in such contexts are not well-understood. Recent data indicate concurrent upregulation in certain tumors of CXCR4, EGF receptor (EGFR), and G protein-coupled receptor kinase 2 (GRK2), a signaling node functionally linked to both receptor types. We have investigated in a model system the effect of the EGFR and GRK2 status on CXCL12/CXCR4-mediated activation of Gi, the earliest step downstream of receptor activation. We find that overexpressed and activated EGFR reduces CXCR4-mediated Gi1 activation and that GRK2 phosphorylation at tyrosine residues is required to exert its inhibitory actions on CXCR4-Gi stimulation, suggesting a shared path of modulation. Our data point to a role for GRK2 in the crosstalk of the CXCR4 and EGFR signal transduction pathways in pathological contexts characterized by concurrent overactivation of these proteins.
ACS Pharmacol Transl Sci 2020 Aug 14
PMID:Modulation of CXCR4-Mediated Gi1 Activation by EGF Receptor and GRK2. 3307 83