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

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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“…The molecular basis of UPR activation by SK2 inhibitors involves elevation of ceramide and changes in lipid composition of the ER membrane have been shown to directly activate IRE1α and PERK independently of lumenal unfolded proteins [5]. Importantly, WallingtonBeddoe et al [2] demonstrate that the findings in MM cell lines are recapitulated in vivo using the 5TGM1 C57BL/ KaLwRij murine model of myeloma.…”

“…Wallington-Beddoe et al [2] in this issue of Oncotarget have analysed a larger gene expression data set from CD138 + bone marrow plasma cells from newly diagnosed myeloma patients compared to normal healthy controls. The authors found that there was increased expression of several genes involved in sphingolipid biosynthesis, including serine palmitoyltransferase, 3-keto-dihydrosphingosine reductase, alkaline ceramidase and SK2.…”

“…The latter might include SK2/S1P-regulation of nuclear histone deacetylase-1/2 (HDAC-1/2) [3] and telomerase reverse transcriptase (TERT) that sustains a replicative immortality programme in cancer cells [4]. Wallington-Beddoe et al [2] have also made a very significant advance by demonstrating that SK2 inhibitors induce a caspase-3-dependent apoptosis of MM cells via an endoplasmic reticulum stress (ER stress)/sustained unfolded protein response (UPR). Moreover, they provide evidence that non-lethal doses of SK2 inhibitors (e.g.…”

“…Prolonged ER stress leads to sustained UPR activation that results in an increase in the expression of the pro-apoptotic transcription factor CHOP. Indeed, using a variety of MM cell lines, Wallington-Beddoe et al [2] demonstrate that bortezomib induces sustained UPR as evidenced by increased BiP, XBP1s, p-eIF2α and CHOP levels.…”

“…First, many of the effects observed with the SK2 inhibitor, K145, on ER stress/UPR and combination with bortezomib are recapitulated with the SK2 inhibitor, ABC294640 [2]. However, a previous study reported that ABC294640 directs c-Myc and Mcl-1 for proteasomal degradation and increases pro-apoptotic Noxa gene transcription to suppress growth of MM [1].…”