Inhibition of IL-6-dependent growth of myeloma cells by an acidic peptide repressing the gp130-mediated activation of Src family kinases

Abstract

An acidic domain (AD) of gp130 was previously found to interact with the Src family kinase (SFK) Hck. Here, the influence of myristoylated peptides derived from this AD was assessed in the mouse myeloma cell line, 7TD1. The IL-6-dependent growth of 7TD1 cells was reduced by B75%, if 100 lM of myristoylated 18mer peptide (18AD) was included in the growth medium, but was unaffected by a control peptide with scrambled sequence (18sc). A similar differential inhibition by peptides 18AD and 18sc was observed for the erythropoietin-dependent growth of BaF-EH cells expressing chimeric erythropoietin receptor-gp130 and human Hck and for the human myeloma cell line INA-6. While the peptide 18AD concentration inhibiting 50% was B30 lM in 7TD1 and BaF-EH cells, peptide 18AD did not significantly inhibit growth of IL-6-independent MM1.S myeloma and OKT1 hybridoma cells or of BaF-EH cells supplied with IL-3. Treatment with 100 lM peptide 18AD caused the same degree or 60% of apoptosis induction as IL-6 deprivation in 7TD1 or INA-6 cells, respectively. Co-immunoprecipitation experiments revealed that peptide 18AD interfered with the association of Hck and gp130 in 7TD1 lysates in a concentrationdependent manner. IL-6-treatment of INA-6 cells induced the kinase activities of Fyn, Lyn and Hck, but not Src, and the IL-6-induced SFK activities were inhibited by peptide 18AD. Expression in 7TD1 cells of a kinaseinactive Hck mutant (K269R) elicited a dominantnegative effect on cell number increases providing further evidence that SFKs are required for gp130 signalling in myeloma cells.

DNMT3A and DNMT3B mediate autocrine hGH repression of plakoglobin gene transcription and consequent phenotypic conversion of mammary carcinoma cells

“…Src, in conjunction with JAK kinases, may therefore be major upstream cellular pathways regulating the expression of the DNMTs and subsequent methylation. Src also has a well-known oncogenic role and is activated by multiple cytokines including IL-6 (Hausherr et al, 2007).…”

Disruption of Src function potentiates Chk1-inhibitor–induced apoptosis in human multiple myeloma cells in vitro and in vivo

“…44 Moreover, kinase-inactive mutants of Hck (K269E or K269R), but not Src (K297R), prevent IL-6-mediated activation of ERK1/2 and inhibit MM-cell proliferation. 15,16 Recently, exposure of serum-starved MM cells to VEGF 165 has been shown to induce activation of Src (manifested by Y418 phosphorylation) and ERK1/2, events abrogated by BMS354825. 17 Such findings suggest that the Src 3 ERK1/2 signaling cascade operates to promote survival mediated by certain growth factors (eg, VEGF and PDGF) in human MM cells.…”

IL-6 and MYC collaborate in plasma cell tumor formation in mice

“…There is a flurry of new compounds that target IL-6 signaling that are ready to enter the clinical trial arena. These include antibodies to IL-6 and IL-6R, 41 small-molecule IL-6R antagonists, 42 gp130-targeting peptides, 43 and small compounds that target signaling events downstream of the fully assembled, functional IL-6R. Additional therapeutic opportunities are provided by compounds that inhibit pathways that can activate IL-6 signaling indirectly, including NF-B, 44 Hsp90, 45 and PI3K/mTOR inhibitors, 46 or that activate pathways that can inhibit IL-6 signaling indirectly, as described for PPAR␥ inhibitors.…”