The Involvement of Canonical NFκB Pathway in Megakaryocyte Differentiation Induction by Nanocurcumin
-
Seyedeh Sahar Mortazavi Farsani
,
Dina Sadeghizadeh
,
Sadegh Babashah
,
Fariba Rad
,
Majid Sadeghizadeh
Abstract
Background: Megakaryopoiesis is characterized by progressive polyploidization and the expression of megakaryocytic markers. Numerous transcription factors and physiological signaling pathways regulate this phenomenon. Megakaryocyte differentiation induction in the K562 cell line and hematopoietic stem cells via nanocurcumin drug has been identified in our previous study. K562 cells are typical Chronic Myelogenous Leukemia (CML) cells that are resistant to apoptosis and express the bcr-abl fusion gene. These cells have the potential to differentiate into erythrocytes and megakaryocytes. Curcumin is well known as a component with strong potential to alter NFκB activity in various cells. NFκB pathway regulates various genes such as apoptotic and immune response genes. The aim of the current study is to evaluate the possible role of nanocurcumin in NFκB pathway regulation during the megakaryopoiesis process in the K562 cell line.
Materials and Methods: Megakaryocyte markers expression and phenotype alteration of nanocurcumin-treated K562 cells have been detected by flow cytometry and microscopy imaging. The nuclear level of the RelA (p65) subunit of NFκB was determined by western blot test in K562 cells during megakaryopoiesis induction via nanocurcumin treatment at different times. The expression of NFκB target genes including c-MYC, BAX, and NQO1 was also analyzed in nanocurcumin-treated K562 cells by quantitative RT-PCR assay at different times.
Results: It was demonstrated that nanocurcumin leads to an increase in NFκB activity transiently during megakaryocyte differentiation, which is followed by a change in the expression of c-MYC, BAX, and NQO1 target genes.
Conclusion: The NFκB pathway can be considered a new pathway for inducing megakaryocyte differentiation by nanocurcumin for the purposes of in vitro and in vivo megakaryopoiesis experiments.
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18. Cui L, Moraga I, Lerbs T, et al. Tuning MPL signaling to influence hematopoietic stem cell differentiation and inhibit essential thrombocythemia progenitors. Proc Natl Acad Sci U S A. 2021;118(2):e2017849118.
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21. Kaur J, Rawat Y, Sood V, et al. Megakaryopoiesis in Dengue virus infected K562 cell promotes viral replication which inhibits endomitosis and accumulation of ROS associated with differentiation. bioRxiv. 2020.
22. Mirgani MT, Isacchi B, Sadeghizadeh M, et al. Dendrosomal curcumin nanoformulation downregulates pluripotency genes via miR-145 activation in U87MG glioblastoma cells. Int J Nanomedicine.2014; 9:403-17.
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24. Geddis AE. Megakaryopoiesis. In: Seminars in hematology: Elsevier; 2010. pp. 212-219.
25. Li C, Peart N, Xuan Z, et al. PMA induces SnoN proteolysis and CD61 expression through an autocrine mechanism. Cell signal. 2014; 26(7):1369-78.
26. Kojok K, El-Kadiry AE-H, Merhi Y. Role of NF-κB in platelet function.
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27. Mussbacher M, Salzmann M, Brostjan C, et al. Cell type-specific roles of NF-κB linking inflammation and thrombosis. Front Immunol. 2019; 10:85.
28. Vallance TM, Sheard JJ, Meng Y, et al. Development and characterization of a novel, megakaryocyte NF-κB reporter cell line for investigating inflammatory responses. J Thromb Haemost. 2021;19(1):107-120.
29. Zhang Y, Sun S, Wang Z, et al. Signaling by the Mpl receptor involves IKK and NF‐κB. J Cell Biochem. 2002;85(3):523-35
30. Ono-Uruga Y, Tozawa K, Matsuoka S, et al. A Novel Mechanism of Megakaryopoiesis from Pre-Adipocytes: Involvement of Transferrin/CD71/TPO Pathways. In: American Society of Hematology Washington, DC; 2014.
31. Meshkini A, Yazdanparast R. Induction of megakaryocytic differentiation in chronic myelogenous leukemia cell K562 by 3-hydrogenkwadaphnin. J Biochem Mol Biol. 2007;40(6):944-51.
32. Huang HL, Chen YC, Huang YC, et al. Lapatinib induces autophagy, apoptosis and megakaryocytic differentiation in chronic myelogenous leukemia K562 cells. PloS one. 2011; 6(12):e29014.
33. Zou X, Qu M, Fang F, et al. Small molecule supplements improve cultured megakaryocyte polyploidization by modulating multiple cell cycle regulators. Biomed Res Int. 2017;2017:2320519.
34. Shehzad A, Lee YS. Molecular mechanisms of curcumin action: signal transduction. Biofactors. 2013; 39(1):27-36.
35. Ghasemi F, Shafiee M, Banikazemi Z, et al. Curcumin inhibits NF-kB and Wnt/β-catenin pathways in cervical cancer cells. Pathol Res Pract. 2019;215(10):152556.
36. Marquardt JU, Gomez-Quiroz L, Camacho LOA, et al. Curcumin effectively inhibits oncogenic NF-κB signaling and restrains stemness features in liver cancer. J Hepatol. 2015;63(3):661-9.
37. Reuter S, Charlet J, Juncker T, et al. Effect of curcumin on nuclear factor κB signaling pathways in human chronic myelogenous K562 leukemia cells. Ann N Y Acad Sci. 2009;1171:436-47.
38. Sahler J, Bernard JJ, Spinelli SL, et al. The Feverfew plant-derived compound, parthenolide enhances platelet production and attenuates platelet activation through NF-κB inhibition. Thromb Res. 2011;127(5):426-34
39. Straus DS, Pascual G, Li M, et al. 15-Deoxy-Δ12, 14-prostaglandin J2 inhibits multiple steps in the NF-κB signaling pathway. Proc Natl Acad Sci U S A. 2000; 97(9): 4844–4849.
40. Wu PS, Yen JH, Wang CY, et al. 8-Hydroxydaidzein, an Isoflavone from Fermented Soybean, Induces Autophagy, Apoptosis, Differentiation, and Degradation of Oncoprotein BCR-ABL in K562 Cells. Biomedicines. 2020; 8(11):506.
41. Zhao M, Joy J, Zhou W, et al. Transcriptional outcomes and kinetic patterning of gene expression in response to NF-κB activation. PLoS Biol. 2018; 16(9):e2006347.
2. Noetzli LJ, French SL, Machlus KR. New insights into the differentiation of megakaryocytes from hematopoietic progenitors. Arterioscler Thromb Vasc Biol. 2019;39(7):1288-1300.
3. Severin S, Ghevaert C, Mazharian A. The mitogen‐activated protein kinase signaling pathways: role in megakaryocyte differentiation. J Thromb Haemost. 2010; 8(1):17-26.
4. Rojnuckarin P, Miyakawa Y, Fox NE, et al. The roles of phosphatidylinositol 3-kinase and protein kinase Cζ for thrombopoietin-induced mitogen-activated protein kinase activation in primary murine megakaryocytes. J Biol Chem. 2001;276(44):41014-22.
5. Hirao A. TPO signal for stem cell genomic integrity. Blood. 2014; 123(4):459-460.
6. Fox N, Lim J, Chen R, et al. F104S c-Mpl responds to a transmembrane domain-binding thrombopoietin receptor agonist: proof of concept that selected receptor mutations in congenital amegakaryocytic thrombocytopenia can be stimulated with alternative thrombopoietic agents. Exp Hematol. 2010; 35(5):384-391.
7. Alcaina PS. Platelet Transfusion: And Update on Challenges and Outcomes. J Blood Med. 2020; 11:19-26.
8. Soltani B, Ghaemi N, Sadeghizadeh M, et al. Redox maintenance and concerted modulation of gene expression and signaling pathways by a nanoformulation of curcumin protects peripheral blood mononuclear cells against gamma radiation. Chem Biol Interact. 2016; 257:81-93.
9. Goel A, A.B. K, Aggarwal BB. Curcumin as “curecumin”: From kitchen to clinic. Biochem Pharmacol. 2008; 75(4):787–809.
10. Javidi MA, Kaeidi A, Mortazavi Farsani SS, et al. Investigating curcumin potential for diabetes cell therapy, in vitro and in vivo study. Life Sci. 2019;239:116908.
11. Babaei E, Sadeghizadeh M, Hassan ZM, et al. Dendrosomal curcumin significantly suppresses cancer cell proliferation in vitro and in vivo. Int Immunopharmacol. 2012;12(1):226-34.
12. Farsani SSM, Sadeghizadeh M, Gholampour MA, et al. Nanocurcumin as a novel stimulator of megakaryopoiesis that ameliorates chemotherapy-induced thrombocytopenia in mice. Life Sci. 2020; 256:117840.
13. Bharti AC, Donato N, Singh S, et al. Curcumin (diferuloylmethane) down-regulates the constitutive activation of nuclear factor-kappa B and IkappaBalpha kinase in human multiple myeloma cells, leading to suppression of proliferation and induction of apoptosis. Blood. 2003; 101(3):1053–62.
14. Carrà G, Torti D, Crivellaro S, et al. The BCR-ABL/NF-κB signal transduction network: a long lasting relationship in Philadelphia positive Leukemias. Oncotarget. 2016; 7(40):66287-66298.
15. Yang Y, Wu J, Wang J. A database and functional annotation of NF-κB target genes. Int J Clin Exp Med. 2016; 9(5):7986-7995.
16. Kim KW, Kim SH, Lee EY, , et al. Extracellular signal-regulated kinase/90-KDA ribosomal S6 kinase/nuclear factor-κB pathway mediates phorbol 12-myristate 13-acetate-induced megakaryocytic differentiation of K562 cells. J Biol Chem. 2001;276(16):13186-91.
17. Zhang Y, Sun S, Wang Z, et al. Signaling by the Mpl Receptor Involves IKK and NF-kB. J Cell Biochem. 2002;85(3):523-35.
18. Cui L, Moraga I, Lerbs T, et al. Tuning MPL signaling to influence hematopoietic stem cell differentiation and inhibit essential thrombocythemia progenitors. Proc Natl Acad Sci U S A. 2021;118(2):e2017849118.
19. Leger DY, Liagre B, Beneytout JL. Role of MAPKs and NF-κB in diosgenin-induced megakaryocytic differentiation and subsequent apoptosis in HEL cells. Intl J Oncol.2006; 28(1):201-207.
20. Jacquel A, Herrant M, Defamie V, et al. A survey of the signaling pathways involved in megakaryocytic differentiation of the human K562 leukemia cell line by molecular and c-DNA array analysis. Oncogene. 2006; 25(5):781-94.
21. Kaur J, Rawat Y, Sood V, et al. Megakaryopoiesis in Dengue virus infected K562 cell promotes viral replication which inhibits endomitosis and accumulation of ROS associated with differentiation. bioRxiv. 2020.
22. Mirgani MT, Isacchi B, Sadeghizadeh M, et al. Dendrosomal curcumin nanoformulation downregulates pluripotency genes via miR-145 activation in U87MG glioblastoma cells. Int J Nanomedicine.2014; 9:403-17.
23. Kruger NJ. The Bradford method for protein quantitation. Methods Mol Biol. 1994;32:9-15.
24. Geddis AE. Megakaryopoiesis. In: Seminars in hematology: Elsevier; 2010. pp. 212-219.
25. Li C, Peart N, Xuan Z, et al. PMA induces SnoN proteolysis and CD61 expression through an autocrine mechanism. Cell signal. 2014; 26(7):1369-78.
26. Kojok K, El-Kadiry AE-H, Merhi Y. Role of NF-κB in platelet function.
Int J Mol Sci. 2019;20(17):4185.
27. Mussbacher M, Salzmann M, Brostjan C, et al. Cell type-specific roles of NF-κB linking inflammation and thrombosis. Front Immunol. 2019; 10:85.
28. Vallance TM, Sheard JJ, Meng Y, et al. Development and characterization of a novel, megakaryocyte NF-κB reporter cell line for investigating inflammatory responses. J Thromb Haemost. 2021;19(1):107-120.
29. Zhang Y, Sun S, Wang Z, et al. Signaling by the Mpl receptor involves IKK and NF‐κB. J Cell Biochem. 2002;85(3):523-35
30. Ono-Uruga Y, Tozawa K, Matsuoka S, et al. A Novel Mechanism of Megakaryopoiesis from Pre-Adipocytes: Involvement of Transferrin/CD71/TPO Pathways. In: American Society of Hematology Washington, DC; 2014.
31. Meshkini A, Yazdanparast R. Induction of megakaryocytic differentiation in chronic myelogenous leukemia cell K562 by 3-hydrogenkwadaphnin. J Biochem Mol Biol. 2007;40(6):944-51.
32. Huang HL, Chen YC, Huang YC, et al. Lapatinib induces autophagy, apoptosis and megakaryocytic differentiation in chronic myelogenous leukemia K562 cells. PloS one. 2011; 6(12):e29014.
33. Zou X, Qu M, Fang F, et al. Small molecule supplements improve cultured megakaryocyte polyploidization by modulating multiple cell cycle regulators. Biomed Res Int. 2017;2017:2320519.
34. Shehzad A, Lee YS. Molecular mechanisms of curcumin action: signal transduction. Biofactors. 2013; 39(1):27-36.
35. Ghasemi F, Shafiee M, Banikazemi Z, et al. Curcumin inhibits NF-kB and Wnt/β-catenin pathways in cervical cancer cells. Pathol Res Pract. 2019;215(10):152556.
36. Marquardt JU, Gomez-Quiroz L, Camacho LOA, et al. Curcumin effectively inhibits oncogenic NF-κB signaling and restrains stemness features in liver cancer. J Hepatol. 2015;63(3):661-9.
37. Reuter S, Charlet J, Juncker T, et al. Effect of curcumin on nuclear factor κB signaling pathways in human chronic myelogenous K562 leukemia cells. Ann N Y Acad Sci. 2009;1171:436-47.
38. Sahler J, Bernard JJ, Spinelli SL, et al. The Feverfew plant-derived compound, parthenolide enhances platelet production and attenuates platelet activation through NF-κB inhibition. Thromb Res. 2011;127(5):426-34
39. Straus DS, Pascual G, Li M, et al. 15-Deoxy-Δ12, 14-prostaglandin J2 inhibits multiple steps in the NF-κB signaling pathway. Proc Natl Acad Sci U S A. 2000; 97(9): 4844–4849.
40. Wu PS, Yen JH, Wang CY, et al. 8-Hydroxydaidzein, an Isoflavone from Fermented Soybean, Induces Autophagy, Apoptosis, Differentiation, and Degradation of Oncoprotein BCR-ABL in K562 Cells. Biomedicines. 2020; 8(11):506.
41. Zhao M, Joy J, Zhou W, et al. Transcriptional outcomes and kinetic patterning of gene expression in response to NF-κB activation. PLoS Biol. 2018; 16(9):e2006347.
| Files | ||
| Issue | Vol 17, No 1 (2023) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijhoscr.v17i1.11709 | |
| Keywords | ||
| Megakaryopoiesis; Nanocurcumin; NFκB pathway; Chronic Myelogenous Leukemia (CML) | ||
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How to Cite
1.
Mortazavi Farsani SS, Sadeghizadeh D, Babashah S, Rad F, Sadeghizadeh M. The Involvement of Canonical NFκB Pathway in Megakaryocyte Differentiation Induction by Nanocurcumin. Int J Hematol Oncol Stem Cell Res. 2023;17(1):18-27.
