Sphingosine kinase 2 inhibition synergises with bortezomib to target myeloma by enhancing endoplasmic reticulum stress

Craig Wallington-Beddoe, Melissa Bennett, Kate Vandyke, Lorena Davies, Julia Zebol, Paul Moretti, Duncan Hewett, Andrew Zannettino, Stuart Pitson

    Research output: Contribution to journalArticle

    20 Citations (Scopus)

    Abstract

    The proteasome inhibitor bortezomib has proven to be invaluable in the treatment of myeloma. By exploiting the inherent high immunoglobulin protein production of malignant plasma cells, bortezomib induces endoplasmic reticulum (ER) stress and the unfolded protein response (UPR), resulting in myeloma cell death. In most cases, however, the disease remains incurable highlighting the need for new therapeutic targets. Sphingosine kinase 2 (SK2) has been proposed as one such therapeutic target for myeloma. Our observations that bortezomib and SK2 inhibitors independently elicited induction of ER stress and the UPR prompted us to examine potential synergy between these agents in myeloma. Targeting SK2 synergistically contributed to ER stress and UPR activation induced by bortezomib, as evidenced by activation of the IRE1 pathway and stress kinases JNK and p38MAPK, thereby resulting in potent synergistic myeloma apoptosis in vitro. The combination of bortezomib and SK2 inhibition also exhibited strong in vivo synergy and favourable effects on bone disease. Therefore, our studies suggest that perturbations of sphingolipid signalling can synergistically enhance the effects seen with proteasome inhibition, highlighting the potential for the combination of these two modes of increasing ER stress to be formally evaluated in clinical trials for the treatment of myeloma patients.

    Original languageEnglish
    Pages (from-to)43602-43616
    Number of pages15
    JournalOncotarget
    Volume8
    Issue number27
    DOIs
    Publication statusE-pub ahead of print - 2017

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  • Cite this

    Wallington-Beddoe, C., Bennett, M., Vandyke, K., Davies, L., Zebol, J., Moretti, P., Hewett, D., Zannettino, A., & Pitson, S. (2017). Sphingosine kinase 2 inhibition synergises with bortezomib to target myeloma by enhancing endoplasmic reticulum stress. Oncotarget, 8(27), 43602-43616. https://doi.org/10.18632/oncotarget.17115