News on: Sphingosine kinase 2 inhibition synergises with bortezomib to target myeloma by enhancing endoplasmic reticulum stress, by Wallington-Beddoe et al. Oncotarget. 2017; doi: 10.18632/oncotarget.17115

Pyne, Nigel J.

Pyne, Susan

University of Strathclyde Institutional Repository

Pyne, Nigel J. and Pyne, Susan (2017) Sphingosine kinase 2 and multiple myeloma. Oncotarget, 8 (24). pp. 43596-43597. ISSN 1949-2553 , 10.18632/oncotarget.17420This version is available at https://strathprints.strath.ac.uk/61524/Strathprints is  designed  to  allow  users  to  access  the  research  output  of  the  University  of Strathclyde. Unless otherwise explicitly stated on the manuscript, Copyright © and Moral Rights for the papers on this site are retained by the individual authors and/or other copyright owners. Please check the manuscript for details of any other licences that may have been applied. You may  not  engage  in  further  distribution  of  the  material  for  any  profitmaking  activities  or  any commercial gain. You may freely distribute both the url (https://strathprints.strath.ac.uk/) and the content of this paper for research or private study, educational, or not-for-profit purposes without prior permission or charge. Any correspondence concerning this service should be sent to the Strathprints administrator: strathprints@strath.ac.ukThe Strathprints institutional repository (https://strathprints.strath.ac.uk) is a digital archive of University of Strathclyde research outputs. It has been developed to disseminate open access research outputs, expose data about those outputs, and enable the management and persistent access to Strathclyde's intellectual output.Oncotarget43596www.impactjournals.com/oncotargetwww.impactjournals.com/oncotarget/              Oncotarget, 2017, Vol. 8, (No. 27), pp: 43596-43597Sphingosine kinase 2 and multiple myelomaNigel J. Pyne and Susan PyneNews on: Sphingosine kinase 2 inhibition synergises with bortezomib to target myeloma by enhancing endoplasmic reticulum stress by Wallington-Beddoe et al. Oncotarget. 2017; doi: 10.18632/oncotarget.17115The survival of patients with Multiple Myeloma (MM) has improved due to the use of chemotherapeutic agents with autologous hematopoietic stem cell transplantation. However, the disease is incurable and relapse may occur within months. In addition, chemo-resistance to agents, such as bortezomib can occur and therefore there is an unmet medical need. Sphingosine kinase 2 (SK2), the enzyme that catalyses formation of the bioactive lipid, sphingosine 1-phosphate (S1P) has UHFHQWO\EHHQLGHQWL¿HGDVDYLDEOHWDUJHWIRUWKHUDSHXWLFintervention in MM [1]. Indeed, the SK2 inhibitor, ABC294640, has been shown to induce the down-regulation of Mcl-1 and c-Myc leading to caspase-3-dependent apoptosis of MM cells [1]. Moreover, SK2 expression levels are increased in bone marrow CD138+ myeloma cells from patients [1]. 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 expression levels of a second sphingosine NLQDVH LVRIRUP6.ZHUHQRWFKDQJHG7KHVH¿QGLQJVsuggest that SK2 is the predominant functional SK isoform in MM, and acts to remove ceramide to limit a ceramide burden and to promote MM cell survival via S1P-dependent mechanisms. 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 PDGHDYHU\ VLJQL¿FDQW DGYDQFHE\GHPRQVWUDWLQJ WKDWSK2 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. K145) and bortezomib can lead to synergistic sustained UPR and CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP)-LQGXFHGDSRSWRVLVRI00FHOOV7KHVH¿QGLQJVDUHYHU\important because they provide mechanistic evidence for the action of SK2 inhibitors in cancer cells. Moreover, they suggest that combined treatment with SK2 inhibitors and bortezomib might allow use of lower doses of each, thereby avoiding/delaying chemo-resistance and LQFUHDVLQJWKHH൵HFWLYHQHVVRIWKHUDSHXWLFLQWHUYHQWLRQLQMM.Bortezomib promotes the accumulation of protein which overwhelms the folding capacity of the ER to initiate ER stress and sustain UPR and which subsequently leads to apoptosis of CD138+ myeloma cells. This involves dissociation of the ER chaperone binding immunoglobulin protein (BiP) from the lumenal domains of ER stress sensors, which are protein kinase R-like (5NLQDVH3(5.LQRVLWROUHTXLULQJNLQDVH,5(Įand activating transcription factor 6 (ATF6). 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 E\ LQFUHDVHG %L3 ;%3V SH,)Į DQG &+23 OHYHOVIn addition, they demonstrate that the SK2 inhibitor, K145, induces ER stress, which is shown by increased H[SUHVVLRQRI;%3VDQGSH,)Į+RZHYHU%L3LVRQO\modestly increased in response to K145 and this provides the molecular basis for the synergism with bortezomib by allowing complementarity in the activation of ER stress sensors that result in CHOP-dependent apoptosis. This is also probably linked with the temporal activation NLQHWLFVRI,5(ĮDQG3(5.,QDGGLWLRQ.LQGXFHVIRE1-dependent alarm activation of JNK and p38 MAPK. 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 WRGLUHFWO\DFWLYDWH ,5(ĮDQG3(5. LQGHSHQGHQWO\RIlumenal unfolded proteins [5]. Importantly, Wallington-%HGGRHHWDO>@GHPRQVWUDWHWKDWWKH¿QGLQJVLQ00FHOOlines are recapitulated in vivo using the 5TGM1 C57BL/KaLwRij murine model of myeloma.7KHVH ¿QGLQJV UDLVH D QXPEHU RI LPSRUWDQWLVVXHV)LUVWPDQ\RIWKHH൵HFWVREVHUYHGZLWKWKH6.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]. This might represent an early event in ER stress via deployment of                        NewsOncotarget43597www.impactjournals.com/oncotargetER-associated degradation (ERAD) that is then switched to CHOP/caspase-3-induced apoptosis in the presence of bortezomib. Second, ABC294640 also inhibits dihydroceramide desaturase (Des1) [6, 7] that we have suggested might be a gate-keeper of the proteasome [6]. Third, we have also shown that the dual SK1/SK2 and Des1 inhibitor, SKi (4-([4-(4-chlorophenyl)thiazol-2-yl] amino) phenol) induces an ER stress/UPR in T-cell lymphoblastic leukemic (T-ALL) cells that results in a protective cell survival autophagy [8]. Indeed, ER stress/835YLD,5(Į-1.LVOLQNHGZLWK%HFOLQUHJXODWLRQthat can orchestrate autophagic responses. In contrast, the SK2 selective inhibitor, (R)-FTY720 methylether failed to induce an ER stress/UPR response yet promoted autophagic death of T-ALL cells [8]. Clearly, the role of ER stress/UPR and regulation by SK2 has some cancer VSHFL¿FFRQWH[WEXWLWZRXOGEHLQWHUHVWLQJWRHYDOXDWHWKHrole of autophagy in the apoptotic process induced by SK2 inhibitors in MM cellsWallington-Beddoe et al. [2] place ER stress/835DWWKHFHQWUHRIVSKLQJROLSLGDFWLRQDQGVSHFL¿FDOO\ceramide/sphingosine/S1P regulation by SK2 in MM. 3HUKDSV PRUH VLJQL¿FDQWO\ WKH\ KDYH GHPRQVWUDWHGtherapeutic potential for combined treatment using SK2 LQKLELWRUVDQGERUWH]RPLE7KHVH¿QGLQJVSURYLGHLPSHWXVfor the development of nM potent SK2 inhibitors that can be translated to the clinic to treat myeloma.Nigel J. Pyne: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, Scotland, UKCorrespondence to: Nigel J. Pyne, email n.j.pyne@strath.ac.ukKeywords: sphingosine 1-phosphate, endoplasmic reticulum stress, unfolded protein response, autophagy, apoptosisReceived: April 17, 2017Published: April 25, 2017REFERENCES1. Venkata, et al. Blood. 2014; 124: 1915-25.2. Wallington-Beddoe, et al. Oncotarget. 2017; doi: 10.18632/oncotarget.17115.3. Hait, et al. Science. 2009; 325: 1254-7.4. Panneer Selvam, et al. Sci Signal. 2015; 8: ra58.5. Volmer, et al. Proc Natl Acad Sci U S A. 2013; 110: 4628-33.6. McNaughton, et al. Oncotarget. 2016; 7: 16663-75. doi: 10.18632/oncotarget.7693.7. Venant, et al. Mol Cancer Ther. 2015; 14: 2744-52.8. Evangelisti, et al. Oncotarget. 2014; 5: 7886-901. doi: 10.18632/oncotarget.2318.Copyright: Pyne 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 repro-duction in any medium, provided the original author and source are credited.

Sphingosine kinase 2 and multiple myeloma

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