Bucala

Cecchinelli

Goncalves Silva

Harazono

Ruvolo

Sakhnevych

Yang

Yasinska

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Alliance of galectin-3 and CD74 biochemical networks as a crucial component of survival machinery operated by human acute myeloid leukaemia cells

Yasinska, Inna M.

Sumbayev, Vadim V.

Kent Academic Repository

Kent Academic RepositoryFull text document (pdf)Copyright & reuseContent in the Kent Academic Repository is made available for research purposes. Unless otherwise stated allcontent is protected by copyright and in the absence of an open licence (eg Creative Commons), permissions for further reuse of content should be sought from the publisher, author or other copyright holder. Versions of researchThe version in the Kent Academic Repository may differ from the final published version. Users are advised to check http://kar.kent.ac.uk for the status of the paper. Users should always cite the published version of record.EnquiriesFor any further enquiries regarding the licence status of this document, please contact: researchsupport@kent.ac.ukIf you believe this document infringes copyright then please contact the KAR admin team with the take-down information provided at http://kar.kent.ac.uk/contact.htmlCitation for published versionYasinska, Inna M. and Sumbayev, Vadim V.  (2019) Alliance of galectin-3 and CD74 biochemicalnetworks as a crucial component of survival machinery operated by human acute myeloid leukaemiacells.   EBioMedicine .    ISSN 2352-3964.DOIhttps://doi.org/10.1016/j.ebiom.2019.05.051Link to record in KARhttps://kar.kent.ac.uk/74464/Document VersionPublisher pdfEBioMedicine xxx (2019) xxxEBIOM-02195; No of Pages 2Contents lists available at ScienceDirectEBioMedicinej ourna l homepage: www.eb iomed ic ine.comCommentaryAlliance of galectin-3 and CD74 biochemical networks as a crucialcomponent of survival machinery operated by human acute myeloidleukaemia cellsInna M. Yasinska, Vadim V. Sumbayev ⁎Medway School of Pharmacy, Universities of Kent and Greenwich, Chatham Maritime, Kent, United KingdomAcute myeloid leukaemia (AML) is a severe systemic malignancy this enzyme (the enzyme has three subunits – structural (A), regulatoryoriginated from self-renewing transformed immature myeloid precur-sors. AML can often be a fatal disease since transformed cells operatehighly effective machinery which allows them to protect themselvesagainst induction of programmed cells death and also to suppressanti-cancer activity of natural killer (NK) and cytotoxic T cells (CTCs)thus evading immune attack [4, 6]. These biochemical networks act asa “multilayer protection cover” for AML cells since even if they areattacked by the immune cells, their killing becomes problematic dueto effectiveness of anti-apoptotic machinery. Therefore, it is cruciallyimportant to understand themechanisms underlying functional activityof anti-apoptotic biochemical networks operated by AML cells in orderto select optimal targets and design new drugs for successful and efﬁ-cient therapy.In the study published in this issue of EBioMedicine, Ruvolo and col-leagues have demonstrated that two biochemical cell survival pathwayscontrolled by galectin-3 (a beta-galactoside-binding protein) and clus-ter of differentiation (CD) 74 (a signalling receptor and a chaperonefor major histocompatibility complex type II proteins which are in-volved in antigen presentation) are cross-linked in a biochemical pro-tein network, which is associated with poor survival of AML patients[7]. Importantly, this invaluable clinical study was performed usingsamples obtained from a large number of AML patients (511 in total)with newly diagnosed disease when malignant cells normally displayhigh pro-survival and immune evasion activities. The study reportsthat galectin-3 expression is prognostic for poor survival rate of AMLpa-tients. Survival rate of AML patients with galectin-3 positive malignantcells was even lower when CD74-dependent signalling networks (inparticular, the one involving transmembrane receptor known asCD44) were active. Intriguingly, the study reported galectin-3 to act asa negative regulator of the protein phosphatase 2A (PP2A), the enzymeinvolved in deactivation of several intracellular signalling cascades (seebelow). It was shown that galectin-3 affects regulatory (B) subunit ofDOI of original article: https://doi.org/10.1016/j.ebiom.2019.05.025.⁎ Corresponding author.E-mail address: V.Sumbayev@kent.ac.uk (V.V. Sumbayev).https://doi.org/10.1016/j.ebiom.2019.05.0512352-3964/© 2019 The Authors. Published by Elsevier B.V. This is an open access article underPlease cite this article as: I.M. Yasinska and V.V. Sumbayev, Alliance of gsurvival machinery op..., EBioMedicine, https://doi.org/10.1016/j.ebiom.20(B) and catalytic (C), [7]).This work is of great value for both basic and clinical AML researchsince it is not just a report of cross-links between biochemical networksbut also a solid clinical veriﬁcation of the evidence obtained in basicin vitro, ex vivo and in vivo studies, which can now be put together inorder to identify the best targets for complex anti-AML therapy.AMLcellsoperateseveralpathwayswhichallowthemtodisablecyto-toxic lymphoid cells (NK and CTCs; summarised in the Fig. 1). This in-cludes implication of CD86-CTLA4 (cytotoxic T-lymphocyte-associatedprotein 4) as well as ligands of programmed cell death protein (PD-L)-PD1pathways [10]. Furthermore,AMLcells operate Tim-3 (T-cell immu-noglobulinandmucin-domaincontainingprotein3)-galectin-9(anothermember of galectin family of proteins, [4]) secretory pathwaywhich im-pairsanti-AMLactivitiesofbothNKcells andCTCs.However, ifAMLcell isattacked by cytotoxic lymphoid cells or subjected to action of endoge-nous (e. g. pro-apoptotic cytokines) or exogenous (e. g. drugs) inducersof apoptosis, it manages to survive with the help of galectin-3 andCD74/CD44 signalling networkswhich appear to be connected [7].From recent reports, we know that galectin-3 is capable to protectmitochondria against defunctionalisation mainly via direct interactionwith proteins from Bcl (B cell lymphoma) -2 family including anti-apoptotic Bcl-2 and pro-apoptotic Bax proteins [5,6,9]. As a result ofthese interactions, Bcl-2 protects mitochondria and Bax loses its capa-bility to cause mitochondrial dysfunction resulting in cytochrome c re-lease followed by caspase-3/caspase cascade activation and apoptosis(Fig. 1). Importantly, galectin-3 has NWGR (Asn-Trp-Gly-Arg) motifspeciﬁc to Bcl-2 family proteins which is necessary for homo- orheterodimerisation of these proteins and thus is capable of interactingwith them [5,9]. Other galectin family members (for example galectin-9), despite their ability to interact with defunctionalised mitochondriain malignant cells [8], do not have this motif and thus do not displaysuch an activity.CD74 and CD44 receptor alliance, activated by the ligand calledmac-rophage migration inhibitory factor (MIF), is capable of activating Ras/ERK (extracellular signal-regulating kinase) and phosphatidylinositol-3 kinase (PI-3 K)/Akt pathways [1, 7]). Also, active CD74 can undergo in-termembrane proteolytic cleavage and activate its intracellular domainwhich displays functional activity. All these pathways activatethe CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).alectin-3 and CD74 biochemical networks as a crucial component of19.05.051Fig. 1. Anti-apoptotic and immune evasion machineries operated by human AML cells. Galectins 3 and 9 are abbreviated as Gal-3 or Gal-9 respectively.2 I.M. Yasinska, V.V. Sumbayev / EBioMedicine xxx (2019) xxxtranscription factors thus leading to expression of various genes, one ofwhich is Bcl-2 ([1], Fig. 1).Tumour suppressor protein p53was reported to block expression ofgalectin-3 by repressing transcription of its gene [2]. However, CD74/CD44 activated by MIF, cause suppression of p53 activity [3] thus mak-ing galectin-3 expression possible (Fig. 1). On the other hand, PP2A, theenzymementioned above, targets crucial components of PI-3 K/Akt andRas/ERK pathways leading to loss of their activities. Ruvolo and Co-Authors have shown that galectin-3 downregulates PP2A activity andthus prevents de-activation of AML cell survival pathways ([7], Fig. 1).So, in addition to its novelty, the work of Ruvolo and colleagues pro-vides excellent clinical veriﬁcation of recently acquired basic knowl-edge. Furthermore, the study clearly demonstrates that galectin-3 andCD74 are promising targets for anti-AML therapy.DisclosureThe authors declared no conﬂicts of interest.References[1] Bucala R, Shachar I. The integral role of CD74 in antigen presentation, MIF signaltransduction, and B cell survival and homeostasis. Mini Rev Med Chem 2014;14:1132–8.Please cite this article as: I.M. Yasinska and V.V. Sumbayev, Alliance of gsurvival machinery op..., EBioMedicine, https://doi.org/10.1016/j.ebiom.20[2] Cecchinelli B, Lavra L, Rinaldo C, Iacovelli S, Gurtner A, Gasbarri A, et al. Repression ofthe antiapoptotic molecule galectin-3 by homeodomain-interacting protein kinase2-activated p53 is required for p53-induced apoptosis. Mol Cell Biol 2006;26:4746–57.[3] De R, Sarkar S, Mazumder S, Debsharma S, Siddiqui AA, Saha SJ, et al. Macrophagemigration inhibitory factor regulates mitochondrial dynamics and cell growth ofhuman cancer cell lines through CD74-NF-kappaB signaling. J Biol Chem 2018;293:19740–60.[4] Goncalves Silva I, Yasinska IM, Sakhnevych SS, Fiedler W, Wellbrock J, Bardelli M,et al. The Tim-3-galectin-9 secretory pathway is involved in the immune escape ofhuman acute myeloid Leukemia cells. EBioMedicine 2017;22:44–57.[5] Harazono Y, Kho DH, Balan V, Nakajima K, Zhang T, Hogan V, et al. Galectin-3 leadsto attenuation of apoptosis through Bax heterodimerization in human thyroid carci-noma cells. Oncotarget 2014;5:9992–10001.[6] Ruvolo PP. Galectin 3 as a guardian of the tumor microenvironment. BiochimBiophys Acta 2016;1863:427–37.[7] Ruvolo PP, Hu CW, Qiu Y, Ruvolo VR, Go RL, Hubner SE, et al. LGALS3 is connected toCD74 in a previously unknown protein network that is associatedwith poor survivalin patients with AML. EBioMedicine 2019. https://doi.org/10.1016/j.ebiom.2019.05.025.[8] Sakhnevych SS, Yasisnka IM, Fasler-Kan E, Sumbayev VV. Mitochondrialdefunctionalization supresses Tim-3-Galectin-9 secretory pathway in human colo-rectal Cancer cells and thus can possibly affect tumor immune escape. FrontPharmacol 2019;10:342.[9] Yang RY, Hsu DK, Liu FT. Expression of galectin-3 modulates T-cell growth and apo-ptosis. Proc Natl Acad Sci U S A 1996;93:6737–42.[10] Yasinska IM, Goncalves Silva I, Sakhnevych S, Gibbs BF, Raap U, Fasler-Kan E, et al.Biochemical mechanisms implemented by human acute myeloid leukemia cells tosuppress host immune surveillance. Cell Mol Immunol 2018;15:989–91.alectin-3 and CD74 biochemical networks as a crucial component of19.05.051

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Alliance of galectin-3 and CD74 biochemical networks as a crucial component of survival machinery operated by human acute myeloid leukaemia cells

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