Login Register Cart 0
Generic placeholder image

Current Chemical Biology

Editor-in-Chief

ISSN (Print): 2212-7968
ISSN (Online): 1872-3136

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

Predicted Role of Acetyl-CoA Synthetase and HAT p300 in Extracellular Lactate Mediated Lactylation in the Tumor: In vitro and In silico Models

Author(s): Rushikesh Patel, Ajay K. Raj, Kiran B. Lokhande, Mrudula Joshi, Kratika Khunteta, Jayanta K. Pal and Nilesh K. Sharma*

Volume 17, Issue 4, 2023

Published on: 29 December, 2023

Page: [203 - 215] Pages: 13

DOI: 10.2174/0122127968256108231226074336

Price: $65

Abstract

Background: As per the Warburg effect, cancer cells are known to convert pyruvate into lactate. The accumulation of lactate is associated with metabolic and epigenetic reprogramming, which has newly been suggested to involve lactylation. However, the role of secreted lactate in modulating the tumor microenvironment through lactylation remains unclear. Specifically, there are gaps in our understanding of the enzyme responsible for converting lactate to lactyl-CoA and the nature of the enzyme that performs lactylation by utilizing lactyl-CoA as a substrate. It is worth noting that there are limited papers focused on metabolite profiling that detect lactate and lactyl-CoA levels intracellularly and extracellularly in the context of cancer cells.

Methods: Here, we have employed an in-house developed vertical tube gel electrophoresis (VTGE) and LC-HRMS assisted profiling of extracellular metabolites of breast cancer cells treated by anticancer compositions of cow urine DMSO fraction (CUDF) that was reported previously. Furthermore, we used molecular docking and molecular dynamics (MD) simulations to determine the potential enzyme that can convert lactate to lactyl-CoA. Next, the histone acetyltransferase p300 (HAT p300) enzyme (PDB ID: 6GYR) was evaluated as a potential enzyme that can bind to lactyl- CoA during the lactylation process.

Results: We collected evidence on the secretion of lactate in the extracellular conditioned medium of breast cancer cells treated by anticancer compositions. MD simulations data projected that acetyl- CoA synthetase could be a potential enzyme that may convert lactate into lactyl-CoA similar to a known substrate acetate. Furthermore, a specific and efficient binding (docking energy -9.6 kcal/mol) of lactyl-CoA with p300 HAT suggested that lactyl-CoA may serve as a substrate for lactylation similar to acetylation that uses acetyl-CoA as a substrate.

Conclusion: In conclusion, our data provide a hint on the missing link for the lactylation process due to lactate in terms of a potential enzyme that can convert lactate into lactyl-CoA. This study helped us to project the HAT p300 enzyme that may use lactyl-CoA as a substrate in the lactylation process of the tumor microenvironment.

Next »
Graphical Abstract

[1]
Levine, A.J.; Puzio-Kuter, A.M. The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes. Science, 2010, 330(6009), 1340-1344.
[http://dx.doi.org/10.1126/science.1193494] [PMID: 21127244]
[2]
Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell, 2011, 144(5), 646-674.
[http://dx.doi.org/10.1016/j.cell.2011.02.013] [PMID: 21376230]
[3]
Lyssiotis, C.A.; Kimmelman, A.C. Metabolic interactions in the tumor microenvironment. Trends Cell Biol., 2017, 27(11), 863-875.
[http://dx.doi.org/10.1016/j.tcb.2017.06.003] [PMID: 28734735]
[4]
Warburg, O. On respiratory impairment in cancer cells. Science, 1956, 124(3215), 269-270.
[http://dx.doi.org/10.1126/science.124.3215.269] [PMID: 13351639]
[5]
Brooks, G.A. The science and translation of lactate shuttle theory. Cell Metab., 2018, 27(4), 757-785.
[http://dx.doi.org/10.1016/j.cmet.2018.03.008] [PMID: 29617642]
[6]
García-Cañaveras, J.C.; Chen, L.; Rabinowitz, J.D. The tumor metabolic microenvironment: Lessons from lactate. Cancer Res., 2019, 79(13), 3155-3162.
[http://dx.doi.org/10.1158/0008-5472.CAN-18-3726] [PMID: 31171526]
[7]
Ngwa, V.M.; Edwards, D.N.; Philip, M.; Chen, J. Microenvironmental metabolism regulates antitumor immunity. Cancer Res., 2019, 79(16), 4003-4008.
[http://dx.doi.org/10.1158/0008-5472.CAN-19-0617] [PMID: 31362930]
[8]
Esteller, M. Epigenetics in cancer. N. Engl. J. Med., 2008, 358(11), 1148-1159.
[http://dx.doi.org/10.1056/NEJMra072067] [PMID: 18337604]
[9]
Kinnaird, A.; Zhao, S.; Wellen, K.E.; Michelakis, E.D. Metabolic control of epigenetics in cancer. Nat. Rev. Cancer, 2016, 16(11), 694-707.
[http://dx.doi.org/10.1038/nrc.2016.82] [PMID: 27634449]
[10]
Sabari, B.R.; Zhang, D.; Allis, C.D.; Zhao, Y. Metabolic regulation of gene expression through histone acylations. Nat. Rev. Mol. Cell Biol., 2017, 18(2), 90-101.
[http://dx.doi.org/10.1038/nrm.2016.140] [PMID: 27924077]
[11]
Sharma, N.K.; Pal, J.K. Metabolic ink lactate modulates epigenomic landscape: A concerted role of pro-tumor microenvironment and macroenvironment during carcinogenesis. Curr. Mol. Med., 2020, 1566524020666200521075252.
[http://dx.doi.org/10.2174/1566524020666200521075252] [PMID: 32436828]
[12]
Zhang, D.; Tang, Z.; Huang, H.; Zhou, G.; Cui, C.; Weng, Y.; Liu, W.; Kim, S.; Lee, S.; Perez-Neut, M.; Ding, J.; Czyz, D.; Hu, R.; Ye, Z.; He, M.; Zheng, Y.G.; Shuman, H.A.; Dai, L.; Ren, B.; Roeder, R.G.; Becker, L.; Zhao, Y. Metabolic regulation of gene expression by histone lactylation. Nature, 2019, 574(7779), 575-580.
[http://dx.doi.org/10.1038/s41586-019-1678-1] [PMID: 31645732]
[13]
Liberti, M.V.; Locasale, J.W. Histone lactylation: A new role for glucose metabolism. Trends Biochem. Sci., 2020, 45(3), 179-182.
[http://dx.doi.org/10.1016/j.tibs.2019.12.004] [PMID: 31901298]
[14]
Varner, E.L.; Trefely, S.; Bartee, D.; von Krusenstiern, E.; Izzo, L.; Bekeova, C.; O’Connor, R.S.; Seifert, E.L.; Wellen, K.E.; Meier, J.L.; Snyder, N.W. Quantification of lactoyl-CoA (lactyl-CoA) by liquid chromatography mass spectrometry in mammalian cells and tissues. Open Biol., 2020, 10(9), 200187.
[http://dx.doi.org/10.1098/rsob.200187] [PMID: 32961073]
[15]
Wang, J.; Yang, P.; Yu, T.; Gao, M.; Liu, D.; Zhang, J.; Lu, C.; Chen, X.; Zhang, X.; Liu, Y. Lactylation of PKM2 suppresses inflammatory metabolic adaptation in pro-inflammatory macrophages. Int. J. Biol. Sci., 2022, 18(16), 6210-6225.
[http://dx.doi.org/10.7150/ijbs.75434] [PMID: 36439872]
[16]
Ye, L.; Jiang, Y.; Zhang, M. Crosstalk between glucose metabolism, lactate production and immune response modulation. Cytokine Growth Factor Rev., 2022, 68, 81-92.
[http://dx.doi.org/10.1016/j.cytogfr.2022.11.001] [PMID: 36376165]
[17]
Dong, H.; Zhang, J.; Zhang, H.; Han, Y.; Lu, C.; Chen, C.; Tan, X.; Wang, S.; Bai, X.; Zhai, G.; Tian, S.; Zhang, T.; Cheng, Z.; Li, E.; Xu, L.; Zhang, K. YiaC and CobB regulate lysine lactylation in Escherichia coli. Nat. Commun., 2022, 13(1), 6628.
[http://dx.doi.org/10.1038/s41467-022-34399-y] [PMID: 36333310]
[18]
Lin, J.; Liu, G.; Chen, L.; Kwok, H.F.; Lin, Y. Targeting lactate-related cell cycle activities for cancer therapy. Semin. Cancer Biol., 2022, 86(Pt 3), 1231-1243.
[http://dx.doi.org/10.1016/j.semcancer.2022.10.009] [PMID: 36328311]
[19]
Gu, J.; Zhou, J.; Chen, Q.; Xu, X.; Gao, J.; Li, X.; Shao, Q.; Zhou, B.; Zhou, H.; Wei, S.; Wang, Q.; Liang, Y.; Lu, L. Tumor metabolite lactate promotes tumorigenesis by modulating MOESIN lactylation and enhancing TGF-β signaling in regulatory T cells. Cell Rep., 2022, 39(12), 110986.
[http://dx.doi.org/10.1016/j.celrep.2022.110986] [PMID: 35732125]
[20]
Megraw, R.E.; Reeves, H.C.; Ajl, S.J. Formation of lactyl-coenzyme A and pyruvyl-coenzyme A from lactic acid by Escherichia coli. J. Bacteriol., 1965, 90(4), 984-988.
[http://dx.doi.org/10.1128/jb.90.4.984-988.1965] [PMID: 5321404]
[21]
Zhang, X.; Mao, Y.; Wang, B.; Cui, Z.; Zhang, Z.; Wang, Z.; Chen, T. Screening, expression, purification and characterization of CoA-transferases for lactoyl-CoA generation. J. Ind. Microbiol. Biotechnol., 2019, 46(7), 899-909.
[http://dx.doi.org/10.1007/s10295-019-02174-6] [PMID: 30963328]
[22]
Rubinow, K.B.; Wall, V.Z.; Nelson, J.; Mar, D.; Bomsztyk, K.; Askari, B.; Lai, M.A.; Smith, K.D.; Han, M.S.; Vivekanandan-Giri, A.; Pennathur, S.; Albert, C.J.; Ford, D.A.; Davis, R.J.; Bornfeldt, K.E. Acyl-CoA synthetase 1 is induced by Gram-negative bacteria and lipopolysaccharide and is required for phospholipid turnover in stimulated macrophages. J. Biol. Chem., 2013, 288(14), 9957-9970.
[http://dx.doi.org/10.1074/jbc.M113.458372] [PMID: 23426369]
[23]
Miao, Z.; Zhao, X.; Liu, X. Hypoxia induced β-catenin lactylation promotes the cell proliferation and stemness of colorectal cancer through the wnt signaling pathway. Exp. Cell Res., 2023, 422(1), 113439.
[http://dx.doi.org/10.1016/j.yexcr.2022.113439] [PMID: 36464122]
[24]
Kanter, J.E.; Kramer, F.; Barnhart, S.; Averill, M.M.; Vivekanandan-Giri, A.; Vickery, T.; Li, L.O.; Becker, L.; Yuan, W.; Chait, A.; Braun, K.R.; Potter-Perigo, S.; Sanda, S.; Wight, T.N.; Pennathur, S.; Serhan, C.N.; Heinecke, J.W.; Coleman, R.A.; Bornfeldt, K.E. Diabetes promotes an inflammatory macrophage phenotype and atherosclerosis through acyl-CoA synthetase 1. Proc. Natl. Acad. Sci., 2012, 109(12), E715-E724.
[http://dx.doi.org/10.1073/pnas.1111600109] [PMID: 22308341]
[25]
Reger, A.S.; Carney, J.M.; Gulick, A.M. Biochemical and crystallographic analysis of substrate binding and conformational changes in acetyl-CoA synthetase. Biochemistry, 2007, 46(22), 6536-6546.
[http://dx.doi.org/10.1021/bi6026506] [PMID: 17497934]
[26]
Schug, Z.T.; Peck, B.; Jones, D.T.; Zhang, Q.; Grosskurth, S.; Alam, I.S.; Goodwin, L.M.; Smethurst, E.; Mason, S.; Blyth, K.; McGarry, L.; James, D.; Shanks, E.; Kalna, G.; Saunders, R.E.; Jiang, M.; Howell, M.; Lassailly, F.; Thin, M.Z.; Spencer-Dene, B.; Stamp, G.; van den Broek, N.J.F.; Mackay, G.; Bulusu, V.; Kamphorst, J.J.; Tardito, S.; Strachan, D.; Harris, A.L.; Aboagye, E.O.; Critchlow, S.E.; Wakelam, M.J.O.; Schulze, A.; Gottlieb, E. Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress. Cancer Cell, 2015, 27(1), 57-71.
[http://dx.doi.org/10.1016/j.ccell.2014.12.002] [PMID: 25584894]
[27]
Liu, M.; Liu, N.; Wang, J.; Fu, S.; Wang, X.; Chen, D. Acetyl-CoA synthetase 2 as a therapeutic target in tumor metabolism. Cancers, 2022, 14(12), 2896.
[http://dx.doi.org/10.3390/cancers14122896] [PMID: 35740562]
[28]
Miller, K.D.; Schug, Z.T. Targeting acetate metabolism: Achilles’ nightmare. Br. J. Cancer, 2021, 124(12), 1900-1901.
[http://dx.doi.org/10.1038/s41416-021-01345-6] [PMID: 33767420]
[29]
Liu, X.; Wang, L.; Zhao, K.; Thompson, P.R.; Hwang, Y.; Marmorstein, R.; Cole, P.A. The structural basis of protein acetylation by the p300/CBP transcriptional coactivator. Nature, 2008, 451(7180), 846-850.
[http://dx.doi.org/10.1038/nature06546] [PMID: 18273021]
[30]
Bowers, E.M.; Yan, G.; Mukherjee, C.; Orry, A.; Wang, L.; Holbert, M.A.; Crump, N.T.; Hazzalin, C.A.; Liszczak, G.; Yuan, H.; Larocca, C.; Saldanha, S.A.; Abagyan, R.; Sun, Y.; Meyers, D.J.; Marmorstein, R.; Mahadevan, L.C.; Alani, R.M.; Cole, P.A. Virtual ligand screening of the p300/CBP histone acetyltransferase: identification of a selective small molecule inhibitor. Chem. Biol., 2010, 17(5), 471-482.
[http://dx.doi.org/10.1016/j.chembiol.2010.03.006] [PMID: 20534345]
[31]
Lasko, L.M.; Jakob, C.G.; Edalji, R.P.; Qiu, W.; Montgomery, D.; Digiammarino, E.L.; Hansen, T.M.; Risi, R.M.; Frey, R.; Manaves, V.; Shaw, B.; Algire, M.; Hessler, P.; Lam, L.T.; Uziel, T.; Faivre, E.; Ferguson, D.; Buchanan, F.G.; Martin, R.L.; Torrent, M.; Chiang, G.G.; Karukurichi, K.; Langston, J.W.; Weinert, B.T.; Choudhary, C.; de Vries, P.; Kluge, A.F.; Patane, M.A.; Van Drie, J.H.; Wang, C.; McElligott, D.; Kesicki, E.; Marmorstein, R.; Sun, C.; Cole, P.A.; Rosenberg, S.H.; Michaelides, M.R.; Lai, A.; Bromberg, K.D. Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours. Nature, 2017, 550(7674), 128-132.
[http://dx.doi.org/10.1038/nature24028] [PMID: 28953875]
[32]
Ortega, E.; Rengachari, S.; Ibrahim, Z.; Hoghoughi, N.; Gaucher, J.; Holehouse, A.S.; Khochbin, S.; Panne, D. Transcription factor dimerization activates the p300 acetyltransferase. Nature, 2018, 562(7728), 538-544.
[http://dx.doi.org/10.1038/s41586-018-0621-1] [PMID: 30323286]
[33]
Li, W.; Wang, Y.; Zhu, L.; Du, S.; Mao, J.; Wang, Y.; Wang, S.; Bo, Q.; Tu, Y.; Yi, Q. The P300/XBP1s/Herpud1 axis promotes macrophage M2 polarization and the development of choroidal neovascularization. J. Cell. Mol. Med., 2021, 25(14), 6709-6720.
[http://dx.doi.org/10.1111/jcmm.16673] [PMID: 34057287]
[34]
Veerasubramanian, P.K.; Shao, H.; Meli, V.S.; Phan, T.A.Q.; Luu, T.U.; Liu, W.F.; Downing, T.L.A. Src-H3 acetylation signaling axis integrates macrophage mechanosensation with inflammatory response. Biomaterials, 2021, 279, 121236.
[http://dx.doi.org/10.1016/j.biomaterials.2021.121236] [PMID: 34753038]
[35]
Lauterbach, M.A.; Hanke, J.E.; Serefidou, M.; Mangan, M.S.J.; Kolbe, C.C.; Hess, T.; Rothe, M.; Kaiser, R.; Hoss, F.; Gehlen, J.; Engels, G.; Kreutzenbeck, M.; Schmidt, S.V.; Christ, A.; Imhof, A.; Hiller, K.; Latz, E. Toll-like receptor signaling rewires macrophage metabolism and promotes histone acetylation via ATP-citrate lyase. Immunity, 2019, 51(6), 997-1011.e7.
[http://dx.doi.org/10.1016/j.immuni.2019.11.009] [PMID: 31851905]
[36]
Cheng, H.; Wang, Z.; Fu, L.; Xu, T. Macrophage polarization in the development and progression of ovarian cancers: An overview. Front. Oncol., 2019, 9, 421.
[http://dx.doi.org/10.3389/fonc.2019.00421] [PMID: 31192126]
[37]
Zhang, H.; Liu, L.; Liu, J.; Dang, P.; Hu, S.; Yuan, W.; Sun, Z.; Liu, Y.; Wang, C. Roles of tumor-associated macrophages in anti-PD-1/PD-L1 immunotherapy for solid cancers. Mol. Cancer, 2023, 22(1), 58.
[http://dx.doi.org/10.1186/s12943-023-01725-x] [PMID: 36941614]
[38]
Zhang, M.; Hei, R.; Zhou, Z.; Xiao, W.; Liu, X.; Chen, Y. Macrophage polarization involved the inflammation of chronic obstructive pulmonary disease by S1P/HDAC1 signaling. Am. J. Cancer Res., 2023, 13(9), 4478-4489.
[PMID: 37818082]
[39]
Kumar, A.; Swami, S.; Sharma, N.K. Distinct DNA metabolism and anti-proliferative effects of goat urine metabolites: An explanation for xeno-tumor heterogeneity. Curr. Chem. Biol., 2020, 14(1), 48-57.
[http://dx.doi.org/10.2174/2212796814666200310102512]
[40]
Kumar, A.; Patel, S.; Bhatkar, D.; Sarode, S.C.; Sharma, N.K. A novel method to detect intracellular metabolite alterations in MCF-7 cells by doxorubicin induced cell death. Metabolomics, 2021, 17(1), 3.
[http://dx.doi.org/10.1007/s11306-020-01755-2] [PMID: 33389242]
[41]
Raj, A.K.; Upadhyay, V.; Lokhande, K.B.; Swamy, K.V.; Bhonde, R.R.; Sarode, S.C.; Sharma, N.K. Free fatty acids from cow urine dmso fraction induce cell death in breast cancer cells without affecting normal GMSCs. Biomedicines, 2023, 11(3), 889.
[http://dx.doi.org/10.3390/biomedicines11030889] [PMID: 36979868]
[42]
Hanwell, M.D.; Curtis, D.E.; Lonie, D.C.; Vandermeersch, T.; Zurek, E.; Hutchison, G.R. Avogadro: An advanced semantic chemical editor, visualization, and analysis platform. J. Cheminform., 2012, 4(1), 17.
[http://dx.doi.org/10.1186/1758-2946-4-17] [PMID: 22889332]
[43]
Morris, G.M.; Huey, R.; Lindstrom, W.; Sanner, M.F.; Belew, R.K.; Goodsell, D.S.; Olson, A.J. AutoDock4 and autodockTools4: Automated docking with selective receptor flexibility. J. Comput. Chem., 2009, 30(16), 2785-2791.
[http://dx.doi.org/10.1002/jcc.21256] [PMID: 19399780]
[44]
Trott, O.; Olson, A.J. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 2010, 31(2), 455-461.
[http://dx.doi.org/10.1002/jcc.21334] [PMID: 19499576]
[45]
DSV3. Discovery Studio Visualizer v3.0. Accelrys software inc. 2010. Available from: https://discover.3ds.com/discovery-studio-visualizer-download
[46]
Release, S. Desmond Molecular Dynamics System; D. E. Shaw Research: New York, NY, 2019.
[47]
Patel, R.; Kumar, A.; Lokhande, K.B.; Swamy, K.V. Molecular docking and simulation studies predict lactyl-CoA as the Substrate for P300 directed lactylation. ChemRxiv, 2020, 2020, 12770360.
[http://dx.doi.org/10.26434/chemrxiv.12770360.v1]

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