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Type: Journal article
Title: Sphingosine kinase 2 inhibition synergises with bortezomib to target myeloma by enhancing endoplasmic reticulum stress
Author: Wallington-Beddoe, C.
Bennett, M.
Vandyke, K.
Davies, L.
Zebol, J.
Moretti, P.
Pitman, M.
Hewett, D.
Zannettino, A.
Pitson, S.
Citation: Oncotarget, 2017; 8(27):43602-43616
Publisher: Impact Journals
Issue Date: 2017
ISSN: 1949-2553
Statement of
Craig T. Wallington-Beddoe, Melissa K. Bennett, Kate Vandyke, Lorena Davies, Julia R. Zebol, Paul A.B. Moretti, Melissa R. Pitman, Duncan R. Hewett, Andrew C.W. Zannettino and Stuart M. Pitson
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.
Keywords: myeloma; endoplasmic reticulum; proteasome inhibitor; sphingosine kinase
Description: Published: April 14, 2017
Rights: Copyright: Wallington-Beddoe et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
RMID: 0030069688
DOI: 10.18632/oncotarget.17115
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Appears in Collections:Medicine publications

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