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Biologic sequelae of c-Jun NH2-terminal kinase (JNK) activation in multiple myeloma cell lines

Oncogene volume 22, pages 8797–8801 (2003)Cite this article

Abstract

Although c-Jun NH2-terminal kinase (JNK) is activated by treatment with therapeutic agents, the biologic sequelae of inhibiting constitutive activation of JNK has not yet been clarified. In this study, we examine the biologic effect of JNK inhibition in multiple myeloma (MM) cell lines. JNK-specific inhibitor SP600125 induces growth inhibition via induction of G1 or G2/M arrest in U266 and MM.1S multiple myeloma cell lines, respectively. Neither exogenous IL-6 nor insulin-like growth factor-1 (IGF-1) overcome SP600125-induced growth inhibition, and IL-6 enhances SP600125-induced G2/M phase in MM.1S cells. Induction of growth arrest is mediated by upregulation of p27Kip1, without alteration of p53 and JNK protein expression. Importantly, SP600125 inhibits growth of MM cells adherent to bone marrow stromal cells (BMSCs). SP600125 induces NF-κB activation in a dose-dependent fashion, associated with phosphorylation of IκB kinase α (IKKα) and degradation of IκBα. In contrast, SP600125 does not affect phosphorylation of STAT3, Akt, and/or ERK. IKK-specific inhibitor PS-1145 inhibits SP600125-induced NF-κB activation and blocks the protective effect of SP600125 against apoptosis. Our data therefore demonstrate for the first time that inhibiting JNK activity induces growth arrest and activates NF-κB in MM cells.

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Acknowledgements

This study is supported by National Institutes of Health Grant PO-1 78378 and RO-1 CA 50947; the Doris Duke Distinguished Clinical Research Scientist Award (KCA); the Multiple Myeloma Research Foundation (THi, THa); and the Cure for Myeloma Research Fund (KCA).

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  1. Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute and Harvard Medical School, 44 Binney Street, Boston, 02115, MA, USA

    Teru Hideshima, Toshiaki Hayashi, Dharminder Chauhan, Masaharu Akiyama, Paul Richardson & Kenneth Anderson

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  1. Teru Hideshima
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  2. Toshiaki Hayashi
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  3. Dharminder Chauhan
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  4. Masaharu Akiyama
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Correspondence to Kenneth Anderson.

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Hideshima, T., Hayashi, T., Chauhan, D. et al. Biologic sequelae of c-Jun NH2-terminal kinase (JNK) activation in multiple myeloma cell lines. Oncogene 22, 8797–8801 (2003). https://doi.org/10.1038/sj.onc.1206919

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