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Activation of NF-κB and upregulation of intracellular anti-apoptotic proteins via the IGF-1/Akt signaling in human multiple myeloma cells: therapeutic implications

Oncogene volume 21, pages 5673–5683 (2002)Cite this article

Abstract

Interleukin-6 (IL-6) and insulin-like growth factor-1 (IGF-1) promote the proliferation of multiple myeloma (MM) cells and protect them against dexamethasone (Dex)-induced apoptosis. We have previously shown that Apo2 ligand/TNF-Related apoptosis inducing ligand (Apo2L/TRAIL) induces apoptosis of MM cells, including cells either sensitive or resistant to Dex and cytotoxic drugs, and overcomes the growth and survival effect of IL-6; conversely, NF-κB transcriptional activity attenuates their Apo2L/TRAIL-sensitivity. In the current study, we demonstrate that IGF-1 stimulates sustained activation of NF-κB and Akt; induces phosphorylation of the FKHRL-1 Forkhead transcription factor; upregulates a series of intracellular anti-apoptotic proteins including FLIP, survivin, cIAP-2, A1/Bfl-1, and XIAP; and decreases Apo2L/TRAIL-sensitivity of MM cells. In contrast, IL-6 does not cause sustained NF-κB activation, induces less pronounced Akt activation and FKHRL-1 phosphorylation than IGF-1, and increases the expression of only survivin. Forced overexpression of constitutively active Akt in MM-1S cells reduced their sensitivity to Apo2L/TRAIL and to doxorubicin (Doxo). In contrast, the Akt inhibitor IL-6-Hydroxymethyl-chiro-inositol 2-(R)-2-O-methyl-3-O-octadecylcarbonate induced cell death of both Dex- and Doxo-sensitive and -resistant cells; opposed the protective effect of constitutive Akt activity against Apo2L/TRAIL; and abrogated the NF-κB activation, increase of anti-apoptotic proteins and protection against Apo2L/TRAIL induced by IGF-1. These findings therefore define an important role of the Akt pathway in modulating tumor cell responsiveness to Apo2L/TRAIL, delineate molecular mechanisms for the survival effects of IGF-1, and characterize differential pathophysiologic sequelae of IGF-1 vs IL-6 on MM cells. Importantly, they provide the basis for future clinical trials in MM combining conventional or novel agents with strategies designed to neutralize IGF-1.

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Acknowledgements

This work was supported by the Multiple Myeloma Research Foundation (CS Mitsiades, N Mitsiades), Lauri Strauss Leukemia Foundation (CS Mitsiades, N Mitsiades), National Institutes of Health Grants RO-1 50947 and PO-1 78378, and the Doris Duke Distinguished Clinical Research Scientist Award (KC Anderson).

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Authors and Affiliations

  1. Department of Adult Oncology, Jerome Lipper Multiple Myeloma Center, Dana Farber Cancer Institute, Harvard Medical School, Boston, 02115, Massachusetts, MA, USA

    Constantine S Mitsiades, Nicholas Mitsiades, Robert Schlossman, Masaharu Akiyama, Dharminder Chauhan, Teru Hideshima, Steven P Treon, Nikhil C Munshi, Paul G Richardson & Kenneth C Anderson

  2. Massachusetts Eye and Ear Infirmary, Harvard Medical School, 234 Charles Street, Boston, 02114, Massachusetts, MA, USA

    Vassiliki Poulaki

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  1. Constantine S Mitsiades
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Correspondence to Kenneth C Anderson.

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Mitsiades, C., Mitsiades, N., Poulaki, V. et al. Activation of NF-κB and upregulation of intracellular anti-apoptotic proteins via the IGF-1/Akt signaling in human multiple myeloma cells: therapeutic implications. Oncogene 21, 5673–5683 (2002). https://doi.org/10.1038/sj.onc.1205664

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