Targeting CD13 (aminopeptidase-N) in turn downregulates ADAM17 by internalization in acute myeloid leukaemia cells

Bouchet, Sandrine; Tang, Ruoping; Fava, Fanny; Legrand, Ollivier; Bauvois, Brigitte

doi:10.18632/oncotarget.1788

Cited by 12 publications

(12 citation statements)

References 71 publications

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“…In particular ADAM17, ADAM15, and ADAM10 have been linked to shedding of various proteins [ 40 , 44 , 45 ]. ADAM17 has also been suggested to interact with CD13 on the surface of myeloid leukemia cells [ 21 ]. ADAM15 has been found to be up-regulated in RA synovium compared to OA, is constitutively expressed by RA FLS, and has been linked to angiogenesis and FLS migration[ 46 – 48 ].…”

Section: Discussionmentioning

confidence: 99%

“…The standard curve was prepared using recombinant human CD13 (R&D Systems, Minneapolis, MN) in block with 10mM EDTA. 1D7 (591.1D7.34, University of Michigan Hybridoma Core), an anti-CD13 monoclonal antibody that was recently described [ 10 ], was biotinylated (Biotin-XX Microscale Protein Labeling Kit, Life Technologies, Carlsbad, CA) and applied overnight [ 21 ]. Streptavidin-HRP (Biolegend, San Diego, CA) was then added.…”

Section: Methodsmentioning

confidence: 99%

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Localization, Shedding, Regulation and Function of Aminopeptidase N/CD13 on Fibroblast like Synoviocytes

et al. 2016

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Aminopeptidase N/CD13 is highly expressed by fibroblast like synoviocytes (FLS) and may play a role in rheumatoid arthritis (RA). CD13 was previously detected in human synovial fluid where it was significantly increased in RA compared to osteoarthritis. In this study we found that CD13 in biological fluids (plasma, synovial fluid, FLS culture supernatant) is present as both a soluble molecule and on extracellular vesicles, including exosomes, as assessed by differential ultracentrifugation and density gradient separation. Having determined CD13 could be released as a soluble molecule from FLS, we examined potential mechanisms by which CD13 might be shed from the FLS membrane. The use of protease inhibitors revealed that CD13 is cleaved from the FLS surface by metalloproteinases. siRNA treatment of FLS revealed one of those proteases to be MMP14. We determined that pro-inflammatory cytokines (TNFα, IFNγ, IL-17) upregulated CD13 mRNA in FLS, which may contribute to the increased CD13 in RA synovium and synovial fluid. Inhibition of CD13 function by either inhibitors of enzymatic activity or anti-CD13 antibodies resulted in decreased growth and diminished migration of FLS. This suggests that CD13 may be involved in the pathogenic hyperplasia of RA FLS. This data expands potential roles for CD13 in the pathogenesis of RA.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Localization, Shedding, Regulation and Function of Aminopeptidase N/CD13 on Fibroblast like Synoviocytes

et al. 2016

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“…The anti-CD13 mAbs WM15 and SJ1D1 were found to bind to surface CD13 on primary blood AML cells but not on cells from patients with chronic lymphocytic leukaemia (CLL) [ 20 , 33 ]. Leukemic AML and CLL cells were exposed ex vivo to NGR-peptides (10–75 μM), and cell death was assessed by the deterioration of cell morphology and PS exposure at various time points.…”

Section: Resultsmentioning

confidence: 99%

The CNGRC-GG-D(KLAKLAK)2 peptide induces a caspase-independent, Ca2+-dependent death in human leukemic myeloid cells by targeting surface aminopeptidase N/CD13

et al. 2015

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The CD13 antigen's binding site for the Asn-Gly-Arg (NGR) motif enables NGR-containing chemotherapeutic drugs to be delivered to CD13-positive tumours. Human CD13-positive acute myeloid leukemia (AML) cells proliferate abnormally and escape death. Here, we show that the CNGRC-GG-D(KLAKLAK)2 peptide induces death in AML cell lines (U937, THP-1, NB4, HL-60) and primary blood cells from AML patients. Cell death was characterized as a caspase-independent mechanism, without DNA fragmentation, but phosphatidylserine externalization and membrane disruption. Our results demonstrate in U937 cells that (i) the NGR-peptide triggers the loss of mitochondrial potential(ΔΨm) and generates superoxide anion (O2−), (ii) N-acetyl-L-cysteine (NAC) and extra/intracellular Ca2+ chelators (BAPTA) prevent both O2− production and cell death, (iii) the Ca2+-channel blocker nifedipine prevents cell death (indicating that Ca2+ influx is the initial death trigger), and (iv) BAPTA, but not NAC, prevents ΔΨm loss (suggesting O2− is a mitochondrial downstream effector). AML cell lines and primary blasts responding to the lethal action of NGR-peptide express promatrix metalloproteinase-12 (proMMP-12) and its substrate progranulin (an 88 kDa cell survival factor). A cell-free assay highlighted proMMP-12 activation by O2−. Accordingly, NGR-peptide's downregulation of 88 kDa progranulin protein was prevented by BAPTA and NAC. Conversely, AML blast resistance to NGR-peptide is associated with the expression of a distinct, 105 kDa progranulin isoform. These results indicate that CNGRC-GG-D(KLAKLAK)2 induces death in AML cells through the Ca2+-mitochondria-O2.-pathway, and support the link between proMMP-12 activation and progranulin cleavage during cell death. Our findings may have implications for the understanding of tumour biology and treatment.

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“…Both CD4 and CD13 are targets for therapeutic intervention. [49][50][51] Indeed, a humanized anti-CD4 mAb, Zanolimumab, has shown promising results in the treatment of reumathoid arthritis, psoriasis, Sezary syndrome and against T cell lymphomas. 49,52 To perform the corresponding bioconjugation with the dibromoxylene system, a previous disulfide reduction step of the mAbs was needed to release reactive thiol groups.…”

Section: Bioconjugationmentioning

confidence: 99%

Bioconjugation through Mesitylene Thiol Alkylation

et al. 2018

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The design and generation of complex multifunctional macromolecular structures by bioconjugation is a hot topic due to increasing interest in conjugates with therapeutic applications. In this regard, the development of efficient, selective, and safe conjugation methods is a major objective. In this report, we describe the use of the bis(bromomethyl)benzene scaffold as a linker for bioconjugation with special emphasis on antibody conjugation. We first performed the monothioalkylation of 1,3,5-tris(bromomethyl)benzene, which rendered the reactive dibromotrimethylbenzyl derivatives to be used in thiol bis-alkylation. Next, we introduced into the linker either a bis(Cys)-containing peptide or anti-CD4 and -CD13 monoclonal antibodies, previously subjected to partial reduction of disulfide bonds. Mass spectrometry, UV-vis spectra, and SDS-PAGE experiments revealed that this bis-alkylating agent for bioconjugation preserved both antibody integrity and antibody-antigen binding affinity, as assessed by flow cytometry. Taken together, our results show that the mesitylene scaffold is a suitable linker for thiol-based bioconjugation reactions. This linker could be applicable in the near future for the preparation of antibody drug conjugates.

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Targeting CD13 (aminopeptidase-N) in turn downregulates ADAM17 by internalization in acute myeloid leukaemia cells

Cited by 12 publications

References 71 publications

Localization, Shedding, Regulation and Function of Aminopeptidase N/CD13 on Fibroblast like Synoviocytes

Localization, Shedding, Regulation and Function of Aminopeptidase N/CD13 on Fibroblast like Synoviocytes

The CNGRC-GG-D(KLAKLAK)2 peptide induces a caspase-independent, Ca2+-dependent death in human leukemic myeloid cells by targeting surface aminopeptidase N/CD13

Bioconjugation through Mesitylene Thiol Alkylation

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