Oncotarget

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

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

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Oncotarget. 2017; 8:43602-43616. https://doi.org/10.18632/oncotarget.17115

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Abstract

Craig T. Wallington-Beddoe1,2,3, Melissa K. Bennett1,2,3, Kate Vandyke2,3,4, Lorena Davies1,2, Julia R. Zebol1,2, Paul A.B. Moretti1,2, Melissa R. Pitman1,2, Duncan R. Hewett3,4, Andrew C.W. Zannettino1,2,3,4,* and Stuart M. Pitson1,2,3,*

1 Center for Cancer Biology, University of South Australia, Adelaide, Australia

2 SA Pathology, Adelaide, Australia

3 School of Medicine, University of Adelaide, Australia

4 South Australian Health and Medical Research Institute, Adelaide, Australia

* Co-senior authorship of this article

Correspondence to:

Andrew C.W. Zannettino, email:

Stuart M. Pitson, email:

Keywords: myeloma, endoplasmic reticulum, proteasome inhibitor, sphingosine kinase

Received: March 29, 2017 Accepted: April 04, 2017 Published: April 14, 2017

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.


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