An inhibitor of the EGF receptor family blocks myeloma cell growth factor activity of HB-EGF and potentiates dexamethasone or anti-IL-6 antibody-induced apoptosis.
We previously found that some myeloma cell lines express the heparin-binding epidermal growth factor-like growth factor (HB-EGF) gene. As the proteoglycan syndecan-1 is an HB-EGF coreceptor as well as a hallmark of plasma cell differentiation and a marker of myeloma cells, we studied the role of HB-EGF on myeloma cell growth. The HB-EGF gene was expressed by bone marrow mononuclear cells in 8 of 8 patients with myeloma, particularly by monocytes and stromal cells, but not by purified primary myeloma cells. Six of 9 myeloma cell lines and 9 of 9 purified primary myeloma cells expressed ErbB1 or ErbB4 genes coding for HB-EGF receptor. In the presence of a low interleukin-6 (IL-6) concentration, HB-EGF stimulated the proliferation of the 6 ErbB1+ or ErbB4+ cell lines, through the phosphatidylinositol 3-kinase/AKT (PI-3K/AKT) pathway. A pan-ErbB inhibitor blocked the myeloma cell growth factor activity and the signaling induced by HB-EGF. This inhibitor induced apoptosis of patients'myeloma cells cultured with their tumor environment. It also increased patients' myeloma cell apoptosis induced by an anti-IL-6 antibody or dexamethasone. The ErbB inhibitor had no effect on the interaction between multiple myeloma cells and stromal cells. It was not toxic for nonmyeloma cells present in patients' bone marrow cultures or for the growth of hematopoietic progenitors. Altogether, these data identify ErbB receptors as putative therapeutic targets in multiple myeloma.
Institut National de la Santé et de la Recherche Médicale (INSERM) U475, Montpellier, France.
Karène
K
Mahtouk
Michel
M
Jourdan
John
J
De Vos
Catherine
C
Hertogh
Geneviève
G
Fiol
Eric
E
Jourdan
Jean-François
JF
Rossi
Bernard
B
Klein
D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000166:cytology; D002448:Cell Adhesion; D002454:Cell Differentiation; D002455:Cell Division; D045744:Cell Line, Tumor; D002469:Cell Separation; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D004357:Drug Synergism; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000378:metabolism* / Q000502:physiology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6 / Q000096:biosynthesis / Q000276:immunology* / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis; D009000:Monocytes / Q000378:metabolism; D009101:Multiple Myeloma / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D066247:Receptor, ErbB-4; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity
D018931:Antineoplastic Agents, Hormonal; D004791:Enzyme Inhibitors; C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; D018950:Lipopolysaccharide Receptors; D004815:Epidermal Growth Factor; D003907:Dexamethasone; D019869:Phosphatidylinositol 3-Kinases; C587689:ERBB4 protein, human; D066246:ErbB Receptors; D066247:Receptor, ErbB-4