Login Register Cart 0
Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Activation of Myosin Phosphatase by Epigallocatechin-Gallate Sensitizes THP-1 Leukemic Cells to Daunorubicin

Author(s): Emese Tóth, Ferenc Erdődi and Andrea Kiss*

Volume 21, Issue 9, 2021

Published on: 17 July, 2020

Page: [1092 - 1098] Pages: 7

DOI: 10.2174/1871520620666200717142315

Price: $65

Abstract

Background: The Myosin Phosphatase (MP) holoenzyme is composed of a Protein Phosphatase type 1 (PP1) catalytic subunit and a regulatory subunit termed Myosin Phosphatase Target subunit 1 (MYPT1). Besides dephosphorylation of myosin, MP has been implicated in the control of cell proliferation via dephosphorylation and activation of the tumor suppressor gene products, retinoblastoma protein (pRb) and merlin. Inhibition of MP was shown to attenuate the drug-induced cell death of leukemic cells by chemotherapeutic agents, while activation of MP might have a sensitizing effect.

Objective: Recently, Epigallocatechin-Gallate (EGCG), a major component of green tea, was shown to activate MP by inducing the dephosphorylation of MYPT1 at phospho-Thr696 (MYPT1pT696), which might confer enhanced chemosensitivity to cancer cells.

Methods: THP-1 leukemic cells were treated with EGCG and Daunorubicin (DNR) and cell viability was analyzed. Phosphorylation of tumor suppressor proteins was detected by Western blotting.

Results: EGCG or DNR (at sub-lethal doses) alone had moderate effects on cell viability, while the combined treatment caused a significant decrease in the number of viable cells by enhancing apoptosis and decreasing proliferation. EGCG plus DNR decreased the phosphorylation level of MYPT1pT696, which was accompanied by prominent dephosphorylation of pRb. In addition, significant dephosphorylation of merlin was observed when EGCG and DNR were applied together.

Conclusion: Our results suggest that EGCG-induced activation of MP might have a regulatory function in mediating the chemosensitivity of leukemic cells via dephosphorylation of tumor suppressor proteins.

Keywords: Myosin phosphatase, EGCG, 67 kDa laminin receptor, retinoblastoma protein, merlin, chemosensitivity.

« Previous Next »
Graphical Abstract

[1]
Gan, R.Y.; Li, H.B.; Sui, Z.Q.; Corke, H. Absorption, metabolism, anti-cancer effect and molecular targets of Epigallocatechin Gallate (EGCG): An updated review. Crit. Rev. Food Sci. Nutr., 2018, 58(6), 924-941.
[http://dx.doi.org/10.1080/10408398.2016.1231168] [PMID: 27645804]
[2]
Saeki, K.; Hayakawa, S.; Nakano, S.; Ito, S.; Oishi, Y.; Suzuki, Y.; Isemura, M. In vitro and in silico studies of the molecular interactions of Epigallocatechin-3-O-gallate (EGCG) with proteins that explain the health benefits of green tea. Molecules, 2018, 23(6)E1295
[http://dx.doi.org/10.3390/molecules23061295] [PMID: 29843451]
[3]
Tachibana, H.; Koga, K.; Fujimura, Y.; Yamada, K. A receptor for green tea polyphenol EGCG. Nat. Struct. Mol. Biol., 2004, 11(4), 380-381.
[http://dx.doi.org/10.1038/nsmb743] [PMID: 15024383]
[4]
Negri, A.; Naponelli, V.; Rizzi, F.; Bettuzzi, S. Molecular targets of Epigallocatechin-Gallate (EGCG): A special focus on signal transduction and cancer. Nutrients, 2018, 10(12)E1936
[http://dx.doi.org/10.3390/nu10121936] [PMID: 30563268]
[5]
Tsukamoto, S.; Huang, Y.; Umeda, D.; Yamada, S.; Yamashita, S.; Kumazoe, M.; Kim, Y.; Murata, M.; Yamada, K.; Tachibana, H. 67-kDa laminin receptor-dependent Protein Phosphatase 2A (PP2A) activation elicits melanoma-specific antitumor activity overcoming drug resistance. J. Biol. Chem., 2014, 289(47), 32671-32681.
[http://dx.doi.org/10.1074/jbc.M114.604983] [PMID: 25294877]
[6]
Kiss, A.; Erdődi, F.; Lontay, B. Myosin phosphatase: Unexpected functions of a long-known enzyme. Biochim. Biophys. Acta Mol. Cell Res., 2019, 1866(1), 2-15.
[http://dx.doi.org/10.1016/j.bbamcr.2018.07.023] [PMID: 30076859]
[7]
Meeusen, B.; Janssens, V. Tumor suppressive protein phosphatases in human cancer: Emerging targets for therapeutic intervention and tumor stratification. Int. J. Biochem. Cell Biol., 2018, 96, 98-134.
[http://dx.doi.org/10.1016/j.biocel.2017.10.002] [PMID: 29031806]
[8]
Bátori, R.; Bécsi, B.; Nagy, D.; Kónya, Z.; Hegedűs, C.; Bordán, Z.; Verin, A.; Lontay, B.; Erdődi, F. Interplay of myosin phosphatase and protein phosphatase-2A in the regulation of endothelial nitric-oxide synthase phosphorylation and nitric oxide production. Sci. Rep., 2017, 7, 44698.
[http://dx.doi.org/10.1038/srep44698] [PMID: 28300193]
[9]
Kolozsvári, B.; Bakó, É.; Bécsi, B.; Kiss, A.; Czikora, Á.; Tóth, A.; Vámosi, G.; Gergely, P.; Erdődi, F. Calcineurin regulates endothelial barrier function by interaction with and dephosphorylation of myosin phosphatase. Cardiovasc. Res., 2012, 96(3), 494-503.
[http://dx.doi.org/10.1093/cvr/cvs255] [PMID: 22869619]
[10]
Kolupaeva, V.; Janssens, V. PP1 and PP2A phosphatases--cooperating partners in modulating retinoblastoma protein activation. FEBS J., 2013, 280(2), 627-643.
[http://dx.doi.org/10.1111/j.1742-4658.2012.08511.x] [PMID: 22299668]
[11]
Cho, H.S.; Suzuki, T.; Dohmae, N.; Hayami, S.; Unoki, M.; Yoshimatsu, M.; Toyokawa, G.; Takawa, M.; Chen, T.; Kurash, J.K.; Field, H.I.; Ponder, B.A.; Nakamura, Y.; Hamamoto, R. Demethylation of RB regulator MYPT1 by histone demethylase LSD1 promotes cell cycle progression in cancer cells. Cancer Res., 2011, 71(3), 655-660.
[http://dx.doi.org/10.1158/0008-5472.CAN-10-2446] [PMID: 21115810]
[12]
Grey, J.; Jones, D.; Wilson, L.; Nakjang, S.; Clayton, J.; Temperley, R.; Clark, E.; Gaughan, L.; Robson, C. Differential regulation of the androgen receptor by protein phosphatase regulatory subunits. Oncotarget, 2017, 9(3), 3922-3935.
[http://dx.doi.org/10.18632/oncotarget.22883] [PMID: 29423094]
[13]
Kiss, A.; Lontay, B.; Bécsi, B.; Márkász, L.; Oláh, E.; Gergely, P.; Erdodi, F. Myosin phosphatase interacts with and dephosphorylates the retinoblastoma protein in THP-1 leukemic cells: Its inhibition is involved in the attenuation of daunorubicin-induced cell death by calyculin-A. Cell. Signal., 2008, 20(11), 2059-2070.
[http://dx.doi.org/10.1016/j.cellsig.2008.07.018] [PMID: 18755268]
[14]
Rubin, S.M. Deciphering the retinoblastoma protein phosphorylation code. Trends Biochem. Sci., 2013, 38(1), 12-19.
[http://dx.doi.org/10.1016/j.tibs.2012.10.007] [PMID: 23218751]
[15]
Dou, Q.P.; An, B.; Will, P.L. Induction of a retinoblastoma phosphatase activity by anticancer drugs accompanies p53-independent G1 arrest and apoptosis. Proc. Natl. Acad. Sci. USA, 1995, 92(20), 9019-9023.
[http://dx.doi.org/10.1073/pnas.92.20.9019] [PMID: 7568064]
[16]
Wang, R.H.; Liu, C.W.; Avramis, V.I.; Berndt, N. Protein phosphatase 1alpha-mediated stimulation of apoptosis is associated with dephosphorylation of the retinoblastoma protein. Oncogene, 2001, 20(43), 6111-6122.
[http://dx.doi.org/10.1038/sj.onc.1204829] [PMID: 11593419]
[17]
Petrilli, A.M.; Fernández-Valle, C. Role of Merlin/NF2 inactivation in tumor biology. Oncogene, 2016, 35(5), 537-548.
[http://dx.doi.org/10.1038/onc.2015.125] [PMID: 25893302]
[18]
Han, Y. Analysis of the role of the Hippo pathway in cancer. J. Transl. Med., 2019, 17(1), 116.
[http://dx.doi.org/10.1186/s12967-019-1869-4] [PMID: 30961610]
[19]
Wu, R.; Yang, H.; Wan, J.; Deng, X.; Chen, L.; Hao, S.; Ma, L. Knockdown of the Hippo transducer YAP reduces proliferation and promotes apoptosis in the Jurkat leukemia cell. Mol. Med. Rep., 2018, 18(6), 5379-5388.
[http://dx.doi.org/10.3892/mmr.2018.9556] [PMID: 30320399]
[20]
Dedinszki, D.; Kiss, A.; Márkász, L.; Márton, A.; Tóth, E.; Székely, L.; Erdődi, F. Inhibition of protein phosphatase-1 and -2A decreases the chemosensitivity of leukemic cells to chemotherapeutic drugs. Cell. Signal., 2015, 27(2), 363-372.
[http://dx.doi.org/10.1016/j.cellsig.2014.11.021] [PMID: 25435424]
[21]
Cao, J.; Han, J.; Xiao, H.; Qiao, J.; Han, M. Effect of tea polyphenol compounds on anticancer drugs in terms of anti-tumor activity, toxicology, and pharmacokinetics. Nutrients, 2016, 8(12)E762
[http://dx.doi.org/10.3390/nu8120762] [PMID: 27983622]
[22]
Lontay, B.; Serfozo, Z.; Gergely, P.; Ito, M.; Hartshorne, D.J.; Erdodi, F. Localization of myosin phosphatase target subunit 1 in rat brain and in primary cultures of neuronal cells. J. Comp. Neurol., 2004, 478(1), 72-87.
[http://dx.doi.org/10.1002/cne.20273] [PMID: 15334650]
[23]
Ahn, J.H.; McAvoy, T.; Rakhilin, S.V.; Nishi, A.; Greengard, P.; Nairn, A.C. Protein kinase A activates protein phosphatase 2A by phosphorylation of the B56delta subunit. Proc. Natl. Acad. Sci. USA, 2007, 104(8), 2979-2984.
[http://dx.doi.org/10.1073/pnas.0611532104] [PMID: 17301223]
[24]
Umeda, D.; Yano, S.; Yamada, K.; Tachibana, H. Involvement of 67-kDa laminin receptor-mediated myosin phosphatase activation in antiproliferative effect of epigallocatechin-3-O-gallate at a physiological concentration on Caco-2 colon cancer cells. Biochem. Biophys. Res. Commun., 2008, 371(1), 172-176.
[http://dx.doi.org/10.1016/j.bbrc.2008.04.041] [PMID: 18423375]
[25]
Narla, G.; Sangodkar, J.; Ryder, C.B. The impact of phosphatases on proliferative and survival signaling in cancer. Cell. Mol. Life Sci., 2018, 75(15), 2695-2718.
[http://dx.doi.org/10.1007/s00018-018-2826-8] [PMID: 29725697]
[26]
Jaffrézou, J.P.; Levade, T.; Bettaïeb, A.; Andrieu, N.; Bezombes, C.; Maestre, N.; Vermeersch, S.; Rousse, A.; Laurent, G. Daunorubicin-induced apoptosis: Triggering of ceramide generation through sphingomyelin hydrolysis. EMBO J., 1996, 15(10), 2417-2424.
[http://dx.doi.org/10.1002/j.1460-2075.1996.tb00599.x] [PMID: 8665849]
[27]
Ruvolo, P.P. Ceramide regulates cellular homeostasis via diverse stress signaling pathways. Leukemia, 2001, 15(8), 1153-1160.
[http://dx.doi.org/10.1038/sj.leu.2402197] [PMID: 11480555]
[28]
Mazhar, S.; Taylor, S.E.; Sangodkar, J.; Narla, G. Targeting PP2A in cancer: Combination therapies. Biochim. Biophys. Acta Mol. Cell Res., 2019, 1866(1), 51-63.
[http://dx.doi.org/10.1016/j.bbamcr.2018.08.020] [PMID: 30401535]
[29]
Chatterjee, J.; Beullens, M.; Sukackaite, R.; Qian, J.; Lesage, B.; Hart, D.J.; Bollen, M.; Köhn, M. Development of a peptide that selectively activates protein phosphatase-1 in living cells. Angew. Chem. Int. Ed. Engl., 2012, 51(40), 10054-10059.
[http://dx.doi.org/10.1002/anie.201204308] [PMID: 22962028]
[30]
Ciccone, M.; Calin, G.A.; Perrotti, D. From the biology of PP2A to the PADs for therapy of hematologic malignancies. Front. Oncol., 2015, 5, 21.
[http://dx.doi.org/10.3389/fonc.2015.00021] [PMID: 25763353]
[31]
Kónya, Z.; Bécsi, B.; Kiss, A.; Tamás, I.; Lontay, B.; Szilágyi, L.; Kövér, K.E.; Erdődi, F. Aralkyl selenoglycosides and related selenosugars in acetylated form activate protein phosphatase-1 and -2A. Bioorg. Med. Chem., 2018, 26(8), 1875-1884.
[http://dx.doi.org/10.1016/j.bmc.2018.02.039] [PMID: 29501414]
[32]
Ménard, S.; Castronovo, V.; Tagliabue, E.; Sobel, M.E. New insights into the metastasis-associated 67 kD laminin receptor. J. Cell. Biochem., 1997, 67(2), 155-165.
[http://dx.doi.org/10.1002/(SICI)1097-4644(19971101)67:2<155:AID-JCB1>3.0.CO;2-W] [PMID: 9328821]
[33]
Britschgi, A.; Simon, H.U.; Tobler, A.; Fey, M.F.; Tschan, M.P. Epigallocatechin-3-gallate induces cell death in acute myeloid leukaemia cells and supports all-trans retinoic acid-induced neutrophil differentiation via death-associated protein kinase 2. Br. J. Haematol., 2010, 149(1), 55-64.
[http://dx.doi.org/10.1111/j.1365-2141.2009.08040.x] [PMID: 20096012]
[34]
Kumazoe, M.; Kim, Y.; Bae, J.; Takai, M.; Murata, M.; Suemasu, Y.; Sugihara, K.; Yamashita, S.; Tsukamoto, S.; Huang, Y.; Nakahara, K.; Yamada, K.; Tachibana, H. Phosphodiesterase 5 inhibitor acts as a potent agent sensitizing acute myeloid leukemia cells to 67-kDa laminin receptor-dependent apoptosis. FEBS Lett., 2013, 587(18), 3052-3057.
[http://dx.doi.org/10.1016/j.febslet.2013.07.041] [PMID: 23916810]
[35]
Montuori, N.; Selleri, C.; Risitano, A.M.; Raiola, A.M.; Ragno, P.; Del Vecchio, L.; Rotoli, B.; Rossi, G. Expression of the 67-kDa laminin receptor in acute myeloid leukemia cells mediates adhesion to laminin and is frequently associated with monocytic differentiation. Clin. Cancer Res., 1999, 5(6), 1465-1472.
[PMID: 10389934]
[36]
Ahmad, N.; Adhami, V.M.; Gupta, S.; Cheng, P.; Mukhtar, H. Role of the retinoblastoma (pRb)-E2F/DP pathway in cancer chemopreventive effects of green tea polyphenol epigallocatechin-3-gallate. Arch. Biochem. Biophys., 2002, 398(1), 125-131.
[http://dx.doi.org/10.1006/abbi.2001.2704] [PMID: 11811957]
[37]
Liberto, M.; Cobrinik, D. Growth factor-dependent induction of p21(CIP1) by the green tea polyphenol, epigallocatechin gallate. Cancer Lett., 2000, 154(2), 151-161.
[http://dx.doi.org/10.1016/S0304-3835(00)00378-5] [PMID: 10806303]
[38]
Henry, D.; Brumaire, S.; Hu, X. Involvement of pRb-E2F pathway in green tea extract-induced growth inhibition of human myeloid leukemia cells. Leuk. Res., 2019, 77, 34-41.
[http://dx.doi.org/10.1016/j.leukres.2018.12.014] [PMID: 30641474]

Rights & Permissions Print Cite
Article Metrics
27
1
© 2024 Bentham Science Publishers | Privacy Policy