scholarly journals Study of Growth Differentiation Factor 15(GDF15) and Some Biochemical Parameters in Multiple Myeloma Patients Subjected to Chemotherapy with Added Paroxetine in-Vitro

2020 ◽  
Vol 23 (2) ◽  
pp. 18-25
Author(s):  
Zahraa A. H. Al-Timeeme ◽  
◽  
Wisam Kadhum H. Alhashemi ◽  
Alaadin Sahham Naji ◽  
Ahmed Fadhil Neama ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Biochemical Parameters ◽  
Growth Differentiation Factor 15 ◽  
Differentiation Factor

The TGF- β Family Member Growth Differentiation Factor 15 (GDF15) Regulates the Self-Renewal of Multiple Myeloma Cancer Stem Cells

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2954-2954
Author(s):  
Toshihiko Tanno ◽  
Akil Merchant ◽  
Jasmin R. Agarwal ◽  
Qiuju Wang ◽  
William Matsui
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
Cancer Stem Cells ◽  
The Self ◽  
Disease Stage ◽  
Dependent Manner ◽  
Self Renewal ◽  
Growth Differentiation Factor 15 ◽  
Differentiation Factor

Abstract Abstract 2954 Multiple myeloma (MM) cancer stem cells (CSCs) possess both enhanced tumorigenic potential and relative drug resistance suggesting they play a major role in disease relapse and progression. Therefore, a better understanding of the processes regulating MM CSCs may lead to the development of novel therapies that prevent tumor regrowth and improve long-term outcomes. Normal stem cells are tightly regulated by factors within the local microenvironment that include both soluble factors and direct contact with accessory cells. However, external factors regulating MM CSCs have not been identified. Recent studies have demonstrated that stromal cells in the MM bone marrow microenvironment secrete growth differentiation factor 15 (GDF15), a member of the TGF-b family. We initially studied the role of this cytokine in the pathogenesis of MM by examining circulating GDF15 levels in MM patients. Compared to healthy volunteers, we found that median GDF15 levels were significantly increased in MM patients (821 vs. 390 pg/ml; n=16; p<0.05) and increased with disease stage (Stage II=585 pg/ml, Stage III=1, 004 pg/ml). To examine the functional effects of GDF15 on MM cells, we cultured human MM cell lines (NCI-H929, RPMI 8226) with recombinant GDF15 and found that it induced the expansion of isolated CD138neg MM CSCs in a dose-dependent manner but had little impact on the growth of CD138+ plasma cells (Fig). Furthermore, GDF15 enhanced clonogenic myeloma growth as evidenced by increased colony formation that was maintained during serial replating, a surrogate for self-renewal. This effect appeared to be GDF15 specific since it could be blocked using anti-GDF15 antibody. Similarly, GDF15 treatment increased the in vitro clonogenic growth of MM CSCs from primary clinical bone marrow specimens. We also investigated the down-stream cellular pathways potentially mediating the effects of GDF15 and found that it activates the AKT signaling pathway known to improve the self-renewal of embryonic (ES) and normal hematopoietic stem cells. GDF15 also induced expression of the SOX2 transcription factor known to be upregulated in CD138neg MM CSCs. Since SOX2 is required for the self-renewal of ES cells and the generation of induced pluripotent stem (iPS) cells, its induction by GDF15 may also increase the self-renewal of MM CSCs. GDF15 is the first soluble factor identified that regulates MM CSCs, and its effects are mediated by the activation of highly conserved self-renewal programs. Disclosures: No relevant conflicts of interest to declare.

Serum Growth Differentiation Factor 15 Levels in Newly Diagnosed Multiple Myeloma Patients

2013 ◽  
Vol 131 (3) ◽  
pp. 173-178 ◽  
Author(s):  
Pinar Tarkun ◽  
Elif Birtas Atesoglu ◽  
Ozgur Mehtap ◽  
Mahmut Mert Musul ◽  
Abdullah Hacihanefioglu
Keyword(s):  
Multiple Myeloma ◽  
Newly Diagnosed ◽  
Growth Differentiation Factor 15 ◽  
Differentiation Factor

scholarly journals Growth Differentiation Factor 15 Maturation Requires Proteolytic Cleavage by PCSK3, -5, and -6

2018 ◽  
Vol 38 (21) ◽  
Author(s):  
Jing Jing Li ◽  
Jian Liu ◽  
Katherine Lupino ◽  
Xueyuan Liu ◽  
Lili Zhang ◽  
...  
Keyword(s):  
Therapeutic Agent ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Proteolytic Cleavage ◽  
Hormone Signaling ◽  
Liver Growth ◽  
Growth Differentiation Factor 15 ◽  
Differentiation Factor

ABSTRACT Growth differentiation factor 15 (GDF15) is a secreted protein with pleotropic functions from the transforming growth factor β (TGF-β) family. GDF15 is synthesized as a precursor and undergoes proteolytic cleavage to generate mature GDF15. The strong appetite-suppressing effect of mature GDF15 makes it an attractive therapeutic agent/target for diseases such as obesity and cachexia. In addition, clinical studies indicate that circulating, mature GDF15 is an independent biomarker for heart failure. We recently found that GDF15 functions as a heart-derived hormone that inhibits liver growth hormone signaling and postnatal body growth in the pediatric period. However, little is known about the mechanism of GDF15 maturation, in particular the enzymes that mediate GDF15 precursor cleavage. We investigated which candidate proteases can cleave GDF15 precursor and generate mature GDF15 in cardiomyocytes in vitro and mouse hearts in vivo. We discovered that three members of the proprotein convertase, subtilisin/kexin-type (PCSK) family, namely, PCSK3, PCSK5, and PCSK6, can efficiently cleave GDF15 precursor, therefore licensing its maturation both in vitro and in vivo. Our studies suggest that PCSK3, -5, and -6 mediate a crucial step of GDF15 maturation through proteolytic cleavage of the precursor. These results also reveal new targets for therapeutic application of GDF15 in treating obesity and cachexia.

Growth Differentiation Factor-15 Is Not Responsible for Decreased Hepcidin Expression in Cases of Ineffective Eythropoiesis.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2674-2674
Author(s):  
Photis Beris ◽  
Olivier Golaz ◽  
Nouri Mensi ◽  
Thomas Matthes ◽  
Christophe Chardot ◽  
...  
Keyword(s):  
Real Time ◽  
Real Time Pcr ◽  
Thalassemia Major ◽  
Beta Thalassemia ◽  
Growth Differentiation Factor 15 ◽  
Hepcidin Expression ◽  
Beta Thalassemia Major ◽  
Differentiation Factor ◽  
Ferritin H

Abstract Background/Aims: There are at least three pathways for hepcidin regulation: iron, inflammation and erythropoiesis. The most complete studies have been carried out on inflammation. Very little is known about hepcidin regulation in erythropoiesis. It has been reported in the literature that ineffective erythropoiesis in beta-thalassemia reduces hepcidin production. In 2006, Toshihiko et al. reported high levels of Growth Differentiation Factor 15 (GDF15) in beta-thalassemia major/intermedia patients. They postulated that this factor, when secreted by erythroblasts at high levels (&gt;5000 pg/ml; normal values 536±222 pg/ml), may be a negative regulator of hepcidin expression. We tested this hypothesis in 3 beta-thalassemia major patients, in 1 patient with post-chemotherapy-induced aplasia and in 3 healthy controls. Methods: Sera were collected from peripheral blood and analysed for their content of GDF15, interleukin-6 (IL-6), iron, transferrin (TRFN), and transferrin soluble receptor (TFSR), as well as for iron transferrin saturation, and ferritin levels. Furthermore, their capacity to induce mRNA hepcidin expression was evaluated in vitro on a hepatic cell line (HuH7 cells). Cells were incubated with tested sera and their mRNA hepcidin expression as well as mRNA RTF1 and ferritin H content were evaluated by real-time PCR in comparison to three housekeeping genes. Informed consent was obtained from all patients. Results: Beta-thalassemia patients showed significantly elevated plasma levels of GDF15 (1771 pg/ml; 24139 pg/ml; and 3859 pg/ml) as did the patient with chemotherapy- induced aplasia (1505 pg/ml). Mean plasma GDF15 levels of the control samples were 299±191 pg/ml. TFSR was &gt;2 mg/ml in beta-thalassemia patients reflecting increased erythropoiesis, was decreased to 0.47 mg/ml in the aplastic patient, while the average in normal controls was 1.11±0.27 mg/ml. Transferrin iron saturation was 100% for beta thalassemia patients and the aplastic patient. Elevated ferritin levels (528; &gt;1500; 389 ug/l) were noted in beta-thalassemia patients as well as in the aplastic patient (≈ 3000 ug/l). In vitro experiments, repeated twice, showed a significant decrease of mRNA hepcidin expression, using real time-PCR, in all 3 beta thalassemia patients; however, in the post-chemotherapy aplastic patient, mRNA hepcidin was significantly increased. In the latter case, high CRP and IL-6 values were found. No modification of mRNA RTF1 or ferritin H was detected in any of the tested patients. Conclusions: Sera from 3 beta thalassemia patients inhibited mRNA hepcidin expression while those from post-chemotherapy aplastic patient increased. All these patients have a high GDF15 expression suggesting that GDF15 is probably not responsible for decreased mRNA hepcidin expression in vitro. The fact that iron status was similar in all the patients studied, indicates that down-regulation of mRNA hepcidin expression is not mediated by iron in cases with increased erythropoiesis. Only the patient with aplasia was found to have an inflammatory state. This relatively moderate inflammation in the absence of erythropoiesis (= negative control of hepcidin) could explain the increased hepcidin expression detected in this patient. Our results underline that the “erythropoietic” mediator of hepcidin expression still needs to be identified since it is probably not GDF15 as has been previously suggested.

scholarly journals Growth/differentiation factor 15 causes TGFβ-activated kinase 1-dependent muscle atrophy in pulmonary arterial hypertension

Thorax ◽  
2018 ◽  
Vol 74 (2) ◽  
pp. 164-176 ◽  
Author(s):  
Benjamin E Garfield ◽  
Alexi Crosby ◽  
Dongmin Shao ◽  
Peiran Yang ◽  
Cai Read ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Muscle Atrophy ◽  
Fibre Diameter ◽  
Muscle Loss ◽  
Growth Differentiation Factor 15 ◽  
Differentiation Factor ◽  
Pulmonary Arterial

IntroductionSkeletal muscle dysfunction is a clinically important complication of pulmonary arterial hypertension (PAH). Growth/differentiation factor 15 (GDF-15), a prognostic marker in PAH, has been associated with muscle loss in other conditions. We aimed to define the associations of GDF-15 and muscle wasting in PAH, to assess its utility as a biomarker of muscle loss and to investigate its downstream signalling pathway as a therapeutic target.MethodsGDF-15 levels and measures of muscle size and strength were analysed in the monocrotaline (MCT) rat, Sugen/hypoxia mouse and in 30 patients with PAH. In C2C12 myotubes the downstream targets of GDF-15 were identified. The pathway elucidated was then antagonised in vivo.ResultsCirculating GDF-15 levels correlated with tibialis anterior (TA) muscle fibre diameter in the MCT rat (Pearson r=−0.61, p=0.003). In patients with PAH, plasma GDF-15 levels of <564 pg/L predicted those with preserved muscle strength with a sensitivity and specificity of ≥80%. In vitro GDF-15 stimulated an increase in phosphorylation of TGFβ-activated kinase 1 (TAK1). Antagonising TAK1, with 5(Z)-7-oxozeaenol, in vitro and in vivo led to an increase in fibre diameter and a reduction in mRNA expression of atrogin-1 in both C2C12 cells and in the TA of animals who continued to grow. Circulating GDF-15 levels were also reduced in those animals which responded to treatment.ConclusionsCirculating GDF-15 is a biomarker of muscle loss in PAH that is responsive to treatment. TAK1 inhibition shows promise as a method by which muscle atrophy may be directly prevented in PAH.Trial registration numberNCT01847716; Results.

Sign in / Sign up

Export Citation Format

Share Document