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Decreased Activity of Blood Acid Sphingomyelinase in the Course of Multiple Myeloma

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Decreased Activity of Blood Acid Sphingomyelinase in the Course of Multiple Myeloma International Journal of Molecular Sciences Article Decreased Activity of Blood Acid Sphingomyelinase in the Course of Multiple Myeloma Marzena W ˛atek 1,2,* , Ewelina Piktel 3, Joanna Barankiewicz 1, Ewa Sierlecka 4, Sylwia Ko´sciołek-Zgódka 4, Anna Chabowska 5, Łukasz Suprewicz 3, Przemysław Wolak 2 , Bonita Durna´s 2, Robert Bucki 2,3 and Ewa Lech-Mara ´nda 1,6 1 Institute of Hematology and Transfusion Medicine, Indiry Gandhi 14, 02-776 Warsaw, Poland; [email protected] (J.B.); [email protected] (E.L.-M.) 2 Department of Microbiology and Immunology, The Faculty of Medicine and Health Sciences of the Jan Kochanowski University in Kielce, Stefana Zeromskiego˙ 5, 25-001 Kielce, Poland; [email protected] (P.W.); [email protected] (B.D.); [email protected] (R.B.) 3 Department of Medical Microbiology and Nanobiomedical Engineering, Medical University of Bialystok, Mickiewicza 2c, 15-222 Bialystok, Poland; [email protected] (E.P.); [email protected] (Ł.S.) 4 Holy Cross Cancer Center, Artwinskiego 4, 25-734 Kielce, Poland; [email protected] (E.S.); [email protected] (S.K.-Z.) 5 Regional Blood Transfusion Center in Bialystok, 15-950 Bialystok, Poland; [email protected] 6 Centre of Postgraduate Medical Education, Marymoncka 99/103, 01-813 Warsaw, Poland * Correspondence: [email protected]; Tel.: +48-41-349-69-09; +48-41-349-69-16 Received: 8 November 2019; Accepted: 27 November 2019; Published: 30 November 2019 Abstract: Acid sphingomyelinase (aSMase) is involved in the generation of metabolites that function as part of the sphingolipid signaling pathway. It catalyzes the breakdown of sphingomyelin into ceramide, a bioactive lipid that, among other roles, is involved in regulation of apoptosis. Dry drop blood test (DBS) and colorimetric 2-step enzymatic assay were used to assess the activity of human blood aSMase, beta-galactosidase, and beta-glucosidase, these enzymes are lysosomal hydrolases that catalyze the degradation of related sphingolipids, of sphingolipid signaling molecules. Blood was collected from a group of healthy volunteers and patients that were diagnosed with multiple myeloma (MM) in various stages of the disease. Additionally, activity of those enzymes in patients diagnosed with other hematological cancers was also assessed. We found that aSMase activity in the blood of patients with MM (at the time of diagnosis) was 305.43 pmol/spot*20 h, and this value was significantly lower (p < 0.030) compared to the healthy group 441.88 pmol/spot*20 h. Our collected data suggest a possible role of aSMase in pathogenesis of MM development. Keywords: myeloma multiple; sphingolipids; acid sphingomyelinase; cell signaling 1. Introduction In multiple myeloma (MM), development of clonal plasmocyte populations defines the progress of the disease. Plasmocytes suppress the normal blood cell line, leading to immunosuppression and impairment of normal hematopoiesis. They also cause lytic bone lesions and impair renal function through several different mechanisms [1]. Understanding the biology of the tumor that leads to the MM progression is crucial for effective treatment [2]. It is known that the genetic predisposition, the inflammation accompanying the disease, and the abnormal immune response, are all involved in the development of MM. Initiating genomic disorders occur during the maturation of B cells, and clonal plasma cells occupy niches in the bone marrow (BM). The early stage of MM is called monoclonal gammopathy of undetermined significance (MGUS). More than 10% of bone marrow involvement is characterized by the next stage of MM termed as an asymptomatic MM. Damage to tissues (mostly Int. J. Mol. Sci. 2019, 20, 6048; doi:10.3390/ijms20236048 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2019, 20, 6048 2 of 14 bones and kidneys) defines a symptomatic disease that requires treatment. Aggressive plasmocyte clones often show complete inactivation of tumor suppressor genes, such as TP53 [2]. Asymptomatic patients should not be treated unless they have end-organ damage. It is necessary to classify patients as having a high-risk or standard-risk disease. Qualification for the risk group is determined by genetic status of abnormal plasmocytes. Hypodiploidy or deletions (del) of chromosome 13 (del [13]), presence of t (4;14), t (14; 16), t (14; 20) translocations, or del (17p) are considered as high-risk factors. Overall, 25% of patients with symptomatic MM are classified as high-risk patients [3]. Interestingly, MGUS and MM are more frequent in patients with a congenital defect of sphingolipid metabolism [4]. Sphingolipids have been known for years as structural molecules of the cell membrane. They have been shown to be involved in many important cell-signaling processes and their production is governed by the different enzymes (Figure1)[ 5]. After synthesis in the endoplasmic reticulum and Golgi apparatus, they are transported to the cell membrane (Figure2 (1)). They participate in the regulation of numerous cellular processes. Sphingolipids regulate growth, differentiation, chemotactic motility, and control cell death (apoptosis). Sphingolipid molecules tend to self-assemble, forming microdomains within the cell membranes, called lipid rafts [6,7] (Figure2 (2)). They are also compounds of various, often contradictory, biological properties. The main secondary messenger of the sphingomyelin (SM) signaling pathway occupying a central role in the sphingolipid metabolism is ceramide (Cer) (Figure2 (3)) [6]. It forms as a result of sphingomyelin cell membrane hydrolysis, by sphingomyelinase enzymes, and its de novo synthesis starts from serine and palmitoyl-CoA. This reaction is catalyzed by the enzyme palmityl transferase and the product of its action is 3-ketosfinganine [8]. Ceramide induces apoptosis, whereas sphingosine-1-phosphate (S1P) plays a pivotal role in cell survival [9]. Figure 1. A schematic representation of sphingolipid metabolism [5]. Arrows indicate the direction of compounds synthesis. Int. J. Mol. Sci. 2019, 20, 6048 3 of 14 Int. J. Mol. Sci. 2018, 19, x FOR PEER REVIEW 3 of 14 Figure 2.2. (1()1) Sphingolipids, Sphingolipids, after after synthesis synthesis in the in endoplasmic the endoplasmic reticulum, reticulum, nucleus, nucleus, and Golgi and apparatus, Golgi apparatus,are transported are transported to cell membrane. to cell (membrane.2) Acid sphingomyelinase (2) Acid sphingomyelinase (aSMase) contributes (aSMase) to contributes fusion of lipid to fusionrafts and of formationlipid rafts of and membrane formation microdomains. of membrane (3) microdomains. aSMase acting on (3 the) aSMase plasma acting membrane on the contribute plasma membraneto ceramide contribute production. to ceramide Figure prepared production. using Figure BioRENDER prepared software. using BioRENDER software. The sphingomyelin signaling pathway pathway was was describe describedd in in lymphoid lymphoid tissue, tissue, spleen, spleen, nerve nerve tissue, tissue, lungs, liver, liver, myocardium, skeletal skeletal muscle, muscle, and and gastrointestinal gastrointestinal mucosa mucosa [10,11]. [10,11]. MetabolicMetabolic linking linking of sphingolipids through mutual intera interactionsctions related to the action of enzymes: sphingosine sphingosine kinases, S1P phosphatases, ceramideceramide synthases, synthases, and and ceramidases, ceramidases, are important are important in normal in normal cell function cell andfunction pathology and pathologyof disease [9of]. Abnormaldisease [9]. sphingolipids Abnormal sphingolipids metabolism is characteristicmetabolism is feature characteristic of Gaucher feature disease, of andGaucher those disease,patient have and increasedthose patient incidence have ofincreased neoplasm incidence based on of population neoplasm data based [4]. on Based popu onlation the results data [4]. of studies Based onregarding the results the incidence of studies of regarding neoplasms the in theincidence group of of patients neoplasms with in Gaucher the group disease, of patients an increased with incidenceGaucher disease,of tumors an inincreased congenital incidence sphingolipidosis of tumors hasin congenital been observed. sphingolipidosis It seems that has disorders been observed. of sphingolipid It seems thatmetabolism disorders in thisof diseasesphingolipid mayconstitute metabolism a model in th ofis cancerdisease pathogenesis may constitute [12]. Clinicala model observations of cancer pathogenesisshowed that in [12]. Gaucher Clinical disease, observations congenital showed disorders th ofat sphingolipid in Gaucher metabolism disease, congenital [4] and damaged disorders GBA1 of sphingolipidenzyme activity metabolism [13] promoted [4] and the damaged occurrence GBA1 of malignant enzyme activity disease, [13] in particular promoted of the MGUS, occurrence MM, and of malignantB-cell lymphomas, disease, in that particular are more of frequent MGUS, thanMM, inand the B-cell healthy lymphomas, population that [12 are], especially more frequent commonly than indescribed the healthy in GD1 population (the most [12], frequent especially Gaucher commonl diseasey typedescribed I) [14 ,15in ].GD1 Nair (the et al.most suggest frequent that Gaucher the basis diseaseof both Gauchertype I) [14,15]. disease-related Nair et al. gammopathiessuggest that the and basis some of both sporadic Gaucher monoclonal disease-related gammopathies gammopathies are the andresult some of long-term sporadic immune monoclonal activation gammopathies by lysolipids are (lysolipid
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