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MNK kinases facilitate c-myc IRES activity in rapamycin-treated multiple myeloma cells

Oncogene volume 32, pages 190–197 (2013)Cite this article

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An Editorial Expression of Concern to this article was published on 25 August 2023

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Abstract

When mTOR inhibitor rapalogs prevent cap-dependent translation of cell-cycle proteins like c-myc, continuing tumor cell growth depends on cap-independent translation, which is mediated by internal ribosome entry sites (IRESes) located in the 5′-UTR (untranslated region) of transcripts. To investigate if rapalog-induced activation of MNK kinases had a role in such IRES activity, we studied multiple myeloma (MM) cells. Rapamycin (RAP)-activated MNK1 kinase activity in MM cell lines and primary specimens by a mitogen-activated protein kinase-dependent mechanism. Pharmacological inhibition of MNK activity or genetic silencing of MNK1 prevented a rapalog-induced upregulation of c-myc IRES activity. Although RAP, used alone, had little effect on myc protein expression, when combined with a MNK inhibitor, myc protein expression was abrogated. In contrast, there was no inhibition of myc RNA, consistent with an effect on myc translation. In a RAP-resistant MM cell lines as well as a resistant primary MM specimen, co-exposure to a MNK inhibitor or MNK1 knockdown significantly sensitized cells for RAP-induced cytoreduction. Studies in MNK-null murine embryonic fibroblasts additionally supported a role for MNK kinases in RAP-induced myc IRES stimulation. These results indicate that MNK kinase activity has a critical role in the fail-safe mechanism of IRES-dependent translation when mTOR is inhibited. As kinase activity also regulated sensitivity to RAP, the data also provide a rationale for therapeutically targeting MNK kinases for combined treatment with mTOR inhibitors.

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Acknowledgements

We thank the UCLA Jonsson Comprehensive Cancer Center vector core lab for assistance in generating the lentiviral shRNA vectors. This work was supported by research funds of the Veteran's Administration, the Multiple Myeloma Research Foundation and the Department of Defense and NIH Grants RO1 CA109312 and RO1 CA111448.

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Authors and Affiliations

  1. Department of Medicine, Greater Los Angeles VA Healthcare Center and Jonsson Comprehensive Cancer Center of the UCLA Medical Center, Los Angeles, CA, USA

    Y Shi, P Frost, B Hoang, Y Yang, R Fukunaga, J Gera & A Lichtenstein

  2. Department of Biochemistry, Laboratory of Biochemistry, Osaka University of Pharmaceutical Sciences, Takatsuki, Japan

    Y Shi, P Frost, B Hoang, Y Yang, R Fukunaga, J Gera & A Lichtenstein

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  1. Y Shi
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  2. P Frost
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  6. J Gera
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Correspondence to A Lichtenstein.

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Shi, Y., Frost, P., Hoang, B. et al. MNK kinases facilitate c-myc IRES activity in rapamycin-treated multiple myeloma cells. Oncogene 32, 190–197 (2013). https://doi.org/10.1038/onc.2012.43

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