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Interleukin-6 activates phosphoinositol-3′ kinase in multiple myeloma tumor cells by signaling through RAS-dependent and, separately, through p85-dependent pathways

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Abstract

The IL-6-induced activation of the phosphatidylinositol-3′ kinase (PI3-K)/AKT cascade in multiple myeloma (MM) cells is critical for tumor cell proliferation and viability. Since the IL-6 receptor does not contain binding sites for the p85 regulatory portion of PI3-K, intermediate molecules must play a role. Coimmunoprecipitation studies in MM cell lines demonstrated the IL-6-induced formation of two independent PI3-K-containing complexes: one containing p21 RAS but not STAT-3 and a second containing STAT-3 but not RAS. Both complexes demonstrated IL-6-induced lipid kinase activity. IL-6 also generated kinase activity in a mutant p110 molecule that could not bind p85. Use of dominant-negative (DN) constructs confirmed the presence of two independent pathways of activation: a DN RAS prevented the IL-6-induced generation of lipid kinase activity in the mutant p110 molecule but had no effect on activity generated in the STAT-3-containing complex. In contrast, a DN p85 prevented the generation of kinase activity in the STAT-3-containing complex but had no effect on activity generated in the p110 molecule. Both DN constructs significantly prevented the IL-6-induced activation of AKT. MM cells expressing activating RAS mutations demonstrated enhanced IL-6-independent growth and constitutive PI3-K activity. These data indicate two potential independent pathways of PI3-K/AKT activation in MM cells: one mediated via signaling through RAS which is independent of p85 and a second mediated via p85 and due to a STAT-3-containing complex.

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Acknowledgements

We thank Dr Julian Downward, Imperial Cancer Research Fund, Dr Erich Gulbins, University of Tuebingen, Germany, Dr Hong-Gang Wang, University of South Florida and Dr Curt Horvath, Mt Sinai School of Medicine, for their generous gifts of plasmids. The parental ANBL-6 MM cell line and stable transfectants expressing mutated N-RAS or K-RAS genes were generous gifts from Dr Brian Van Ness, Minneapolis, MN, USA.

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  1. Department of Medicine, West LA VA-UCLA Medical Center and Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, 90073, CA, USA

    Jung-hsin Hsu, Yijiang Shi, Patrick Frost, Huajun Yan, Bao Hoang, Sanjai Sharma, Joseph Gera & Alan Lichtenstein

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  1. Jung-hsin Hsu
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  2. Yijiang Shi
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Correspondence to Alan Lichtenstein.

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Hsu, Jh., Shi, Y., Frost, P. et al. Interleukin-6 activates phosphoinositol-3′ kinase in multiple myeloma tumor cells by signaling through RAS-dependent and, separately, through p85-dependent pathways. Oncogene 23, 3368–3375 (2004). https://doi.org/10.1038/sj.onc.1207459

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