General Research Article

Mesenchymal Stem Cells Promote Caspase Expression in Molt-4 Leukemia Cells Via GSK-3α/Β and ERK1/2 Signaling Pathways as a Therapeutic Strategy

Author(s): Ezzatollah Fathi* and Ilja Vietor*

Volume 21, Issue 1, 2021

Published on: 05 October, 2020

Page: [81 - 88] Pages: 8

DOI: 10.2174/1566523220666201005111126

Price: $65

Abstract

Background: Mesenchymal stem cells (MSCs) are considered an interesting tool in cell therapy due to their unique features such as self-renewal, multi-potency, and pluripotency. The multifunctional properties of these cells are being investigated in many studies. The current research examined the influence of MSCs on the Molt-4 cell line as acute lymphoblastic leukemia (ALL) cells.

Methods: MSCs were cultured, characterized, and co-cultured with Molt-4 cells in a trans-well system. Then, cultured Molt-4 alone and Molt-4 co-cultured with MSCs (10:1) were collected on day 7 and subjected to western blotting for protein expression assessment. Telomerase activity as well as cell senescence, were investigated by PCR-ELISA TRAP assay and β-galactosidase activity measurement, respectively.

Results: It was found that MSCs resulted in a significant increase in the pro-caspase-8 and cleaved-caspase 8 and 9 expression levels. Furthermore, protein expression levels of GSK-3α/β and ERK1/2 were significantly decreased. The results also showed that MSCs caused significant decreases and increases in telomerase and β-galactosidase enzyme activity of Molt-4 cells, respectively.

Conclusion: It was concluded that MSCs co-cultured with Molt-4 cells could be involved in the promotion of Molt-4 cell apoptosis and cell senescence via caspase-8, 9 cascade and GSK-3α/β and ERK1/2 signaling pathways.

Keywords: Mesenchymal stem cells, caspase 8 and 9, apoptosis, GSK-3α/β and ERK1/2 signaling pathways, stem cell-based therapy.

« Previous
Graphical Abstract

[1]
Perrot P, Rousseau J, Bouffaut A-L, et al. Safety concern between autologous fat graft, mesenchymal stem cell and osteosarcoma recurrence. PLoS One 2010; 5(6): e10999.
[http://dx.doi.org/10.1371/journal.pone.0010999] [PMID: 20544017]
[2]
Rajabi H, Hosseini V, Rahimzadeh S, Seyfizadeh N, Aslani S, Abhari A. Current status of used protocols for mesenchymal stem cell differentiation: a focus on insulin producing, osteoblast-like and neural cells. Curr Stem Cell Res Ther 2019; 14(7): 570-8.
[http://dx.doi.org/10.2174/1574888X14666190318111614] [PMID: 30887929]
[3]
Valenti MT, Mori A, Malerba G, Dalle Carbonare L. Mesenchymal stem cells: A new diagnostic tool? World J Stem Cells 2015; 7(5): 789-92.
[http://dx.doi.org/10.4252/wjsc.v7.i5.789] [PMID: 26131309]
[4]
Waterman RS, Tomchuck SL, Henkle SL, Betancourt AM. A new mesenchymal stem cell (MSC) paradigm: Polarization into a pro-inflammatory MSC1 or an Immunosuppressive MSC2 phenotype. PLoS One 2010; 5(4): e10088.
[http://dx.doi.org/10.1371/journal.pone.0010088] [PMID: 20436665]
[5]
Zhu N, Wang H, Wei J, et al. NR2F2 regulates bone marrow-derived mesenchymal stem cell-promoted proliferation of Reh cells. Mol Med Rep 2016; 14(2): 1351-6.
[http://dx.doi.org/10.3892/mmr.2016.5389] [PMID: 27314877]
[6]
Lin HD, Fong CY, Biswas A, Choolani M, Bongso A. Human umbilical cord wharton’s jelly stem cell conditioned medium induces tumoricidal effects on lymphoma cells through hydrogen peroxide mediation. J Cell Biochem 2016; 117(9): 2045-55.
[http://dx.doi.org/10.1002/jcb.25501] [PMID: 27392313]
[7]
Zimmerlin L, Donnenberg AD, Rubin JP, Basse P, Landreneau RJ, Donnenberg VS. Regenerative therapy and cancer: in vitro and in vivo studies of the interaction between adipose-derived stem cells and breast cancer cells from clinical isolates. Tissue Eng Part A 2011; 17(1-2): 93-106.
[http://dx.doi.org/10.1089/ten.tea.2010.0248] [PMID: 20673000]
[8]
Fathi E, Sanaat Z, Farahzadi R. Mesenchymal stem cells in acute myeloid leukemia: A focus on mechanisms involved and therapeutic concepts. Blood Res 2019; 54(3): 165-74.
[http://dx.doi.org/10.5045/br.2019.54.3.165] [PMID: 31730689]
[9]
Klopp AH, Gupta A, Spaeth E, Andreeff M, Marini F III. Concise review: Dissecting a discrepancy in the literature: Do mesenchymal stem cells support or suppress tumor growth? Stem Cells 2011; 29(1): 11-9.
[http://dx.doi.org/10.1002/stem.559] [PMID: 21280155]
[10]
Papaccio F, Paino F, Regad T, Papaccio G, Desiderio V, Tirino V. Concise review: cancer cells, cancer stem cells, and mesenchymal stem cells: influence in cancer development. Stem Cells Transl Med 2017; 6(12): 2115-25.
[http://dx.doi.org/10.1002/sctm.17-0138] [PMID: 29072369]
[11]
Calorini L, Bianchini F. Environmental control of invasiveness and metastatic dissemination of tumor cells: the role of tumor cell-host cell interactions. Cell Commun Signal 2010; 8(1): 24.
[http://dx.doi.org/10.1186/1478-811X-8-24] [PMID: 20822533]
[12]
Zhang HM, Zhang LS. Influence of human bone marrow mesenchymal stem cells on proliferation of chronic myeloid leukemia cells. Chin J Cancer 2009; 28(1): 29-32.
[PMID: 19448412]
[13]
Paino F, La Noce M, Di Nucci D, et al. Human adipose stem cell differentiation is highly affected by cancer cells both in vitro and in vivo: Implication for autologous fat grafting. Cell Death Dis 2017; 8(1): e2568.
[http://dx.doi.org/10.1038/cddis.2016.308] [PMID: 28102844]
[14]
Fonseka M, Ramasamy R, Tan BC, Seow HF. Human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSC) inhibit the proliferation of K562 (human erythromyeloblastoid leukaemic cell line). Cell Biol Int 2012; 36(9): 793-801.
[http://dx.doi.org/10.1042/CBI20110595] [PMID: 22335239]
[15]
Fathi E, Valipour B, Sanaat Z, Nozad Charoudeh H, Farahzadi R. Interleukin-6, -8, and TGF-β Secreted from Mesenchymal Stem Cells Show Functional Role in Reduction of Telomerase Activity of Leukemia Cell via Wnt5a/β-Catenin and P53 Pathways. Adv Pharm Bull 2020; 10(2): 307-14.
[http://dx.doi.org/10.34172/apb.2020.037] [PMID: 32373501]
[16]
Wei Z, Chen N, Guo H, et al. Bone marrow mesenchymal stem cells from leukemia patients inhibit growth and apoptosis in serum-deprived K562 cells. J Exp Clin Cancer Res 2009; 28(1): 141.
[http://dx.doi.org/10.1186/1756-9966-28-141] [PMID: 19883517]
[17]
Tian K, Yang S, Ren Q, et al. p38 MAPK contributes to the growth inhibition of leukemic tumor cells mediated by human umbilical cord mesenchymal stem cells. Cell Physiol Biochem 2010; 26(6): 799-808.
[http://dx.doi.org/10.1159/000323973] [PMID: 21220911]
[18]
Fathi E, Farahzadi R, Sheikhzadeh N. Immunophenotypic characterization, multi-lineage differentiation and aging of zebrafish heart and liver tissue-derived mesenchymal stem cells as a novel approach in stem cell-based therapy. Tissue Cell 2019; 57: 15-21.
[http://dx.doi.org/10.1016/j.tice.2019.01.006] [PMID: 30947959]
[19]
Farahzadi R, Fathi E, Vietor I. Mesenchymal stem cells could be considered as a candidate for further studies in cell-based therapy of Alzheimer’s disease via targeting the signaling pathways. ACS Chem Neurosci 2020; 11(10): 1424-35.
[http://dx.doi.org/10.1021/acschemneuro.0c00052] [PMID: 32310632]
[20]
Fathi E, Farahzadi R. Zinc sulphate mediates the stimulation of cell proliferation of rat adipose tissue-derived mesenchymal stem cells under high intensity of EMF exposure. Biol Trace Elem Res 2018; 184(2): 529-35.
[http://dx.doi.org/10.1007/s12011-017-1199-4] [PMID: 29189996]
[21]
Montazersaheb S, Kazemi M, Nabat E, Nielsen PE, Hejazi MS. Downregulation of TdT expression through splicing modulation by antisense peptide nucleic acid (PNA). Curr Pharm Biotechnol 2019; 20(2): 168-78.
[http://dx.doi.org/10.2174/1389201020666190206202650] [PMID: 30727883]
[22]
Aminizadeh N, Tiraihi T, Mesbah-Namin SA, Taheri T. Stimulation of cell proliferation by glutathione monoethyl ester in aged bone marrow stromal cells is associated with the assistance of TERT gene expression and telomerase activity. In Vitro Cell Dev Biol Anim 2016; 52(7): 772-81.
[http://dx.doi.org/10.1007/s11626-016-0021-5] [PMID: 27251157]
[23]
Li W, Zhao X, Zou S, Ma Y, Zhang K, Zhang M. Scanning assay of β-galactosidase activity. Prikl Biokhim Mikrobiol 2012; 48(6): 668-72.
[PMID: 23330395]
[24]
Secchiero P, Zorzet S, Tripodo C, et al. Human bone marrow mesenchymal stem cells display anti-cancer activity in SCID mice bearing disseminated non-Hodgkin’s lymphoma xenografts. PLoS One 2010; 5(6): e11140.
[http://dx.doi.org/10.1371/journal.pone.0011140] [PMID: 20585401]
[25]
Gholizadeh-Ghaleh Aziz S, Fathi E, Rahmati-Yamchi M, Akbarzadeh A, Fardyazar Z, Pashaiasl M. An update clinical application of amniotic fluid-derived stem cells (AFSCs) in cancer cell therapy and tissue engineering. Artif Cells Nanomed Biotechnol 2017; 45(4): 765-74.
[http://dx.doi.org/10.1080/21691401.2016.1216857] [PMID: 27684534]
[26]
Tran C, Damaser MS. Stem cells as drug delivery methods: application of stem cell secretome for regeneration. Adv Drug Deliv Rev 2015; 82-83: 1-11.
[http://dx.doi.org/10.1016/j.addr.2014.10.007] [PMID: 25451858]
[27]
Stellavato A, La Noce M, Corsuto L, et al. Hybrid complexes of high and low molecular weight hyaluronans highly enhance HASCs differentiation: implication for facial bioremodelling. Cell Physiol Biochem 2017; 44(3): 1078-92.
[http://dx.doi.org/10.1159/000485414] [PMID: 29179206]
[28]
Larijani B, Esfahani EN, Amini P, et al. Stem cell therapy in treatment of different diseases. Acta Med Iran 2012; 50(2): 79-96.
[PMID: 22359076]
[29]
Karantalis V, DiFede DL, Gerstenblith G, et al. Autologous mesenchymal stem cells produce concordant improvements in regional function, tissue perfusion, and fibrotic burden when administered to patients undergoing coronary artery bypass grafting: The prospective randomized study of mesenchymal stem cell therapy in patients undergoing cardiac surgery (PROMETHEUS) trial. Circ Res 2014; 114(8): 1302-10.
[http://dx.doi.org/10.1161/CIRCRESAHA.114.303180] [PMID: 24565698]
[30]
Okolie O, Irvin DM, Bago JR, et al. Intra-cavity stem cell therapy inhibits tumor progression in a novel murine model of medulloblastoma surgical resection. PLoS One 2018; 13(7): e0198596.
[http://dx.doi.org/10.1371/journal.pone.0198596] [PMID: 29990322]
[31]
Ganta C, Chiyo D, Ayuzawa R, et al. Rat umbilical cord stem cells completely abolish rat mammary carcinomas with no evidence of metastasis or recurrence 100 days post-tumor cell inoculation. Cancer Res 2009; 69(5): 1815-20.
[http://dx.doi.org/10.1158/0008-5472.CAN-08-2750] [PMID: 19244122]
[32]
Yang C, Lei D, Ouyang W, Ren J, Li H, Hu J, et al. Conditioned media from human adipose tissue-derived mesenchymal stem cells and umbilical cord-derived mesenchymal stem cells efficiently induced the apoptosis and differentiation in human glioma cell lines in vitro. BioMed research international 2014; 109389.
[http://dx.doi.org/10.1155/2014/109389]
[33]
Cetintas VB, Aktug H, Oltulu F, Keskinoglu A, Del BE, Castello DT. The effects of mesenchymal stem cells on lymphoblastic leukemia cell proliferation. J BUON 2014; 19(4): 1006-7.
[PMID: 25536609]
[34]
Eggenhofer E, Luk F, Dahlke MH, Hoogduijn MJ. The life and fate of mesenchymal stem cells. Front Immunol 2014; 5: 148.
[http://dx.doi.org/10.3389/fimmu.2014.00148] [PMID: 24904568]
[35]
Reikvam H, Hatfield KJ, Fredly H, Nepstad I, Mosevoll KA, Bruserud Ø. The angioregulatory cytokine network in human acute myeloid leukemia - from leukemogenesis via remission induction to stem cell transplantation. Eur Cytokine Netw 2012; 23(4): 140-53.
[http://dx.doi.org/10.1684/ecn.2012.0322] [PMID: 23328436]
[36]
Blau O, Baldus CD, Hofmann W-K, Thiel G, Nolte F, Burmeister T, et al. Mesenchymal stromal cells of myelodysplastic syndrome and acute myeloid leukemia patients have distinct genetic abnormalities compared with leukemic blasts. Blood 2011; 118(20): 5583-92.
[http://dx.doi.org/10.1182/blood-2011-03-343467]
[37]
Ehrhardt H, Wachter F, Maurer M, Stahnke K, Jeremias I. Important role of caspase-8 for chemosensitivity of ALL cells. Clin Cancer Res 2011; 17(24): 7605-13.
[http://dx.doi.org/10.1158/1078-0432.CCR-11-0513] [PMID: 22010212]
[38]
Brazvan B, Farahzadi R, Mohammadi SM, et al. Key immune cell cytokines affects the telomere activity of cord blood cells in vitro. Adv Pharm Bull 2016; 6(2): 153-61.
[http://dx.doi.org/10.15171/apb.2016.022] [PMID: 27478776]
[39]
Fathi E, Charoudeh HN, Sanaat Z, Farahzadi R. Telomere shortening as a hallmark of stem cell senescence. Stem Cell Investig 2019; 6: 7.
[http://dx.doi.org/10.21037/sci.2019.02.04] [PMID: 31019963]
[40]
Mai W, Kawakami K, Shakoori A, et al. Deregulated GSK3β sustains gastrointestinal cancer cells survival by modulating human telomerase reverse transcriptase and telomerase. Clin Cancer Res 2009; 15(22): 6810-9.
[http://dx.doi.org/10.1158/1078-0432.CCR-09-0973] [PMID: 19903789]
[41]
Beurel E, Blivet-Van Eggelpoël M-J, Kornprobst M, et al. Glycogen synthase kinase-3 inhibitors augment TRAIL-induced apoptotic death in human hepatoma cells. Biochem Pharmacol 2009; 77(1): 54-65.
[http://dx.doi.org/10.1016/j.bcp.2008.09.026] [PMID: 18938143]
[42]
Janson V, Johansson A, Grankvist K. Resistance to caspase-8 and-9 fragments in a malignant pleural mesothelioma cell line with acquired cisplatin-resistance. Cell Death & Dis 2010; 1(9): e78.
[http://dx.doi.org/10.1038/cddis.2010.54]
[43]
Ruvolo PP. GSK-3 as a novel prognostic indicator in leukemia. Adv Biol Regul 2017; 65: 26-35.
[http://dx.doi.org/10.1016/j.jbior.2017.05.001] [PMID: 28499784]
[44]
Abrahamsson AE, Geron I, Gotlib J, et al. Glycogen synthase kinase 3β missplicing contributes to leukemia stem cell generation. Proc Natl Acad Sci USA 2009; 106(10): 3925-9.
[http://dx.doi.org/10.1073/pnas.0900189106] [PMID: 19237556]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy