title: Targeting CD13 (aminopeptidase-N) in turn downregulates ADAM17 by internalization in acute myeloid leukaemia cells.
abstract: Secreted matrix metalloproteinases (MMP)-2 and MMP-9 and membrane-anchored aminopeptidase-N/CD13 are abnormally expressed in human acute myeloid leukaemia (AML). We previously showed that CD13 ligation by anti-CD13 monoclonal antibodies can induce apoptosis in AML cells. Here, we assessed ADAM17 expression in primary blood blasts CD13+CD33+ from patients with AML. Primary AML cells expressed ADAM17 transcript and its surface expression was higher in subtype M4 (myelomonocytic) and M5 (monocytic) AML specimens than in M0 and M1/M2 (early and granulocytic) specimens. In AML cell lines defining distinct AML subfamilies (HL-60/M2, NB4/M3, THP-1/M5, U937/M5) and primary AML cells cultured ex vivo, anti-CD13 antibodies downregulated surface CD13 and ADAM17 without affecting MMP-2/-9 release. Knockdown of CD13 by siRNA prevented anti-CD13-mediated ADAM17 downregulation, indicating that CD13 is required for ADAM17 downregulation. Soluble ADAM17 was not detected in the medium of anti-CD13 treated cells, suggesting that ADAM17 was not shed. After ligation by anti-CD13, CD13 and ADAM17 were internalized. Subsequently, we found that ADAM17 interacts with CD13. We postulate that the interaction of ADAM17 with CD13 and its downregulation following CD13 engagement has important implications in AML for the known roles of ADAM17 in tumour-associated cell growth, migration and invasion.
authors.affiliation: INSERM U1138, Université Pierre et Marie Curie, Université Paris-Descartes, Centre de Recherche des Cordeliers, Paris, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Bouchet
authors.affiliation: INSERM U938, Centre de Recherche de Saint-Antoine, Paris, France. Service d'Hématologie, Hôpital St Antoine, Paris, France.
authors.forename: Ruoping
authors.initials: R
authors.lastname: Tang
authors.affiliation: INSERM U938, Centre de Recherche de Saint-Antoine, Paris, France. Service d'Hématologie, Hôpital St Antoine, Paris, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Fava
authors.affiliation: INSERM U938, Centre de Recherche de Saint-Antoine, Paris, France. Service d'Hématologie, Hôpital St Antoine, Paris, France.
authors.forename: Ollivier
authors.initials: O
authors.lastname: Legrand
authors.affiliation: INSERM U1138, Université Pierre et Marie Curie, Université Paris-Descartes, Centre de Recherche des Cordeliers, Paris, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Bauvois
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000072198:ADAM17 Protein; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018826:CD13 Antigens / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D004705:Endocytosis; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D018922:HL-60 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D034622:RNA Interference; D013997:Time Factors; D014162:Transfection; D020298:U937 Cells; D055815:Young Adult
chemical_list: D018826:CD13 Antigens; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human