title: A subset of bone marrow stromal cells regulate ATP-binding cassette gene expression via insulin-like growth factor-I in a leukemia cell line.
abstract: The importance of the insulin-like growth factor, IGF, as a signaling axis in cancer development, progression and metastasis is highlighted by its effects on cancer cells, notably proliferation and acquired resistance. The role of the microenvironment within which cancer cells evolve and which mediates this effect is far from clear. Here, the involvement of IGF-I in inducing multidrug resistance in a myeloid leukemia cell line, grown in the presence of bone marrow-derived stromal cells called 'Hospicells' (BMH), is demonstrated. We found that i) drug sensitive as well as resistant leukemia cells express IGF-I and its receptor IGF-IR. However, the resistant cells were found to secrete high levels of IGF-I. ii) Presence of exogenous IGF-I promoted cell proliferation, which decreased when an inhibitor of IGF-IR (picropodophyllin, PPP) was added. iii) BMH and IGF-I are both involved in the regulation of genes of the ATP binding cassette (ABC) related to resistance development (MDR1, MRP1, MRP2, MRP3 and BCRP). iv) The levels of ABC gene expression by leukemia cells were found to increase in the presence of increasing numbers of BMH. However, these levels decreased when IGF-IR was inhibited by addition of PPP. v) Co-culture of the drug-sensitive leukemia cells with BMH induced protection against the action of daunorubicin. This chemoresistance was amplified by the presence of IGF-I whereas it decreased when IGF-IR was inhibited. Our results underline the role of microenvironment in concert with the IGF-1 pathway in conferring drug resistance to leukemia cells.
authors.affiliation: UMR, Paris Diderot, Paris 7 University, Lariboisiere Hospital, INSERM U965, Paris, France.
authors.forename: Nadia
authors.initials: N
authors.lastname: Benabbou
authors.affiliation: UMR, Paris Diderot, Paris 7 University, Lariboisiere Hospital, INSERM U965, Paris, France.
authors.forename: Pezhman
authors.initials: P
authors.lastname: Mirshahi
authors.affiliation: UMR, Paris Diderot, Paris 7 University, Lariboisiere Hospital, INSERM U965, Paris, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Bordu
authors.affiliation: Department of Hematology, Saint-Antoine Hospital, Paris, France.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Faussat
authors.affiliation: Tumor Bank 'Leukemia', Saint-Antoine Hospital, Paris, France.
authors.forename: Ruoping
authors.initials: R
authors.lastname: Tang
authors.affiliation: UMR, Paris Diderot, Paris 7 University, Lariboisiere Hospital, INSERM U965, Paris, France.
authors.forename: Amu
authors.initials: A
authors.lastname: Therwath
authors.affiliation: UMR, Paris Diderot, Paris 7 University, Lariboisiere Hospital, INSERM U965, Paris, France.
authors.forename: Jeannette
authors.initials: J
authors.lastname: Soria
authors.affiliation: Department of Hematology, Saint-Antoine Hospital, Paris, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Marie
authors.affiliation: UMR, Paris Diderot, Paris 7 University, Lariboisiere Hospital, INSERM U965, Paris, France.
authors.forename: Massoud
authors.initials: M
authors.lastname: Mirshahi
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003630:Daunorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D007938:Leukemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000494:pharmacology; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D018528:ATP-Binding Cassette Transporters; C000597236:IGF1R protein, human; D017451:Receptors, Somatomedin; C415032:picropodophyllin; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D011034:Podophyllotoxin; D003630:Daunorubicin
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