Isoform-Specific Role of Akt Kinase in Cancer and its Selective Targeting by Potential Anticancer Natural Agents

Author(s): Nand Kishor Roy, Javadi Monisha, Anuj Kumar Singh, Ganesan Padmavathi, Ajaikumar B. Kunnumakkara*

Journal Name: The Natural Products Journal

Volume 10 , Issue 3 , 2020

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: Akt kinase is a serine/threonine kinase that plays an important role in different cellular processes such as cell proliferation, apoptosis, glucose metabolism, transcription, and cell migration. It has three isoforms (Akt1, 2, and 3) that have distinct and sometimes contrasting functions in different cancers. However, to date, most of the inhibitors are directed against Akt kinase generally which would not serve the purpose due to the lack of isoform selectivity and offtarget toxicity. Therefore, the present study is an elementary step towards the demarcation of the natural inhibitors available from food sources and dietary supplements using in silico methods.

Objective: To demarcate the natural agents and general Akt kinase inhibitors into Akt isoformspecific inhibitors.

Methods: The genetic alterations data for Akt isoforms were obtained from The Cancer Genome Atlas datasets. The protein sequence alignment was achieved using PRALINE program. The modeling of Akt3 protein and its evaluation was performed by ModWeb Server and PROCHECK program, respectively. The docking was performed by using Schrödinger Glide software.

Results: Differential pattern of genetic alterations of Akt isoforms was observed in different cancers. The protein sequence alignment has shown both the conserved as well as the non- conserved region of Akt isoforms. The structure of Akt3 was successfully modeled and evaluated. Finally, with the help of molecular docking, the natural agents and general Akt inhibitors have been segregated into Akt isoform-specific inhibitors based on the derived Glide Score (GScore).

Conclusion: Isoform-specific inhibition of Akt would have huge clinical significance and research should be commenced in preclinical and clinical settings.

Keywords: Natural agents, Akt isoforms, homology modeling, ramachandran plot, docking, schrödinger glide.

[1]
Ranaware, A.M.; Banik, K.; Deshpande, V.; Padmavathi, G.; Roy, N.K.; Sethi, G.; Fan, L.; Kumar, A.P.; Kunnumakkara, A.B. Magnolol: A neolignan from the magnolia family for the prevention and treatment of cancer. Int. J. Mol. Sci., 2018, 19(8), 2362.
[http://dx.doi.org/10.3390/ijms19082362] [PMID: 30103472]
[2]
Roy, N.K.; Deka, A.; Bordoloi, D.; Mishra, S.; Kumar, A.P.; Sethi, G.; Kunnumakkara, A.B. The potential role of boswellic acids in cancer prevention and treatment. Cancer Lett., 2016, 377(1), 74-86.
[http://dx.doi.org/10.1016/j.canlet.2016.04.017] [PMID: 27091399]
[3]
Steelman, L.S.; Stadelman, K.M.; Chappell, W.H.; Horn, S.; Bäsecke, J.; Cervello, M.; Nicoletti, F.; Libra, M.; Stivala, F.; Martelli, A.M.; McCubrey, J.A. Akt as a therapeutic target in cancer. Expert Opin. Ther. Targets, 2008, 12(9), 1139-1165.
[http://dx.doi.org/10.1517/14728222.12.9.1139] [PMID: 18694380]
[4]
Madhunapantula, S.V.; Mosca, P.J.; Robertson, G.P. The Akt signaling pathway: an emerging therapeutic target in malignant melanoma. Cancer Biol. Ther., 2011, 12(12), 1032-1049.
[http://dx.doi.org/10.4161/cbt.12.12.18442] [PMID: 22157148]
[5]
Fortier, A-M.; Asselin, E.; Cadrin, M. Functional specificity of Akt isoforms in cancer progression. Biomol. Concepts, 2011, 2(1-2), 1-11.
[http://dx.doi.org/10.1515/bmc.2011.003] [PMID: 25962016]
[6]
Liao, Y.; Hung, M-C. Physiological regulation of Akt activity and stability. Am. J. Transl. Res., 2010, 2(1), 19-42.
[PMID: 20182580]
[7]
Franke, T.F. PI3K/Akt: getting it right matters. Oncogene, 2008, 27(50), 6473-6488.
[http://dx.doi.org/10.1038/onc.2008.313] [PMID: 18955974]
[8]
Laine, J.; Künstle, G.; Obata, T.; Noguchi, M. Differential regulation of Akt kinase isoforms by the members of the TCL1 oncogene family. J. Biol. Chem., 2002, 277(5), 3743-3751.
[http://dx.doi.org/10.1074/jbc.M107069200] [PMID: 11707444]
[9]
Roy, N.K.; Bordoloi, D.; Monisha, J.; Padmavathi, G.; Kotoky, J.; Golla, R.; Kunnumakkara, A.B. Specific targeting of Akt Kinase isoforms: Taking the precise path for prevention and treatment of cancer. Curr. Drug Targets, 2017, 18(4), 421-435.
[http://dx.doi.org/10.2174/1389450117666160307145236] [PMID: 26953242]
[10]
Frazzetto, M.; Suphioglu, C.; Zhu, J.; Schmidt-Kittler, O.; Jennings, I.G.; Cranmer, S.L.; Jackson, S.P.; Kinzler, K.W.; Vogelstein, B.; Thompson, P.E. Dissecting isoform selectivity of PI3K inhibitors: the role of non-conserved residues in the catalytic pocket. Biochem. J., 2008, 414(3), 383-390.
[http://dx.doi.org/10.1042/BJ20080512] [PMID: 18489260]
[11]
Vogiatzi, P.; Giordano, A. Following the tracks of AKT1 gene. Cancer Biol. Ther., 2007, 6(10), 1521-1524.
[http://dx.doi.org/10.4161/cbt.6.10.4834] [PMID: 17921701]
[12]
Simossis, V. A.; Heringa, J. PRALINE: A multiple sequence alignment toolbox that integrates homology-extended and secondary structure information Nucleic Acids Res, 2005, 33(Web Server), W289-W294.
[http://dx.doi.org/10.1093/nar/gki390]
[13]
Sánchez, R.; Sali, A. Large-scale protein structure modeling of the Saccharomyces cerevisiae genome. Proc. Natl. Acad. Sci. USA, 1998, 95(23), 13597-13602.
[http://dx.doi.org/10.1073/pnas.95.23.13597] [PMID: 9811845]
[14]
Pearson, W.R. Flexible sequence similarity searching with the FASTA3 program package. Methods Mol. Biol., 2000, 132, 185-219.
[PMID: 10547837]
[15]
Berman, H.M.; Westbrook, J.; Feng, Z.; Gilliland, G.; Bhat, T.N.; Weissig, H.; Shindyalov, I.N.; Bourne, P.E. The protein data bank. Nucleic Acids Res., 2000, 28(1), 235-242.
[http://dx.doi.org/10.1093/nar/28.1.235] [PMID: 10592235]
[16]
Šali, A.; Blundell, T.L. Comparative protein modelling by satisfaction of spatial restraints. J. Mol. Biol., 1993, 234(3), 779-815.
[http://dx.doi.org/10.1006/jmbi.1993.1626] [PMID: 8254673]
[17]
Laskowski, R.A.; MacArthur, M.W.; Moss, D.S.; Thornton, J.M. IUCr. PROCHECK: A Program to check the stereochemical quality of protein structures. J. Appl. Cryst., 1993, 26(2), 283-291.
[http://dx.doi.org/10.1107/S0021889892009944]
[18]
Schrödinger 2013.
[19]
Huang, X.; Begley, M.; Morgenstern, K.A.; Gu, Y.; Rose, P.; Zhao, H.; Zhu, X. Crystal structure of an inactive Akt2 kinase domain. Structure, 2003, 11(1), 21-30.
[http://dx.doi.org/10.1016/S0969-2126(02)00937-1] [PMID: 12517337]
[20]
Maruthanila, V.L.; Elancheran, R.; Roy, N.K.; Bhattacharya, A.; Kunnumakkara, A.B.; Kabilan, S.; Kotoky, J. In Silico molecular modelling of selected natural ligands and their binding features with estrogen receptor alpha. Curr. Comput. Aided. Drug Des., 2018, 15(1), 89-96.
[21]
Elancheran, R.; Saravanan, K.; Choudhury, B.; Divakar, S.; Kabilan, S.; Ramanathan, M.; Das, B.; Devi, R.; Kotoky, J. Design and development of oxobenzimidazoles as novel androgen receptor antagonists. Med. Chem. Res., 2016, 25(4), 539-552.
[http://dx.doi.org/10.1007/s00044-016-1504-3]
[22]
Friesner, R.A.; Murphy, R.B.; Repasky, M.P.; Frye, L.L.; Greenwood, J.R.; Halgren, T.A.; Sanschagrin, P.C.; Mainz, D.T. Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J. Med. Chem., 2006, 49(21), 6177-6196.
[http://dx.doi.org/10.1021/jm051256o] [PMID: 17034125]
[23]
Tripathi, S.K.; Muttineni, R.; Singh, S.K. Extra precision docking, free energy calculation and molecular dynamics simulation studies of CDK2 inhibitors. J. Theor. Biol., 2013, 334, 87-100.
[http://dx.doi.org/10.1016/j.jtbi.2013.05.014] [PMID: 23727278]
[24]
Hao, W.; Hu, Y.; Niu, C.; Huang, X.; Chang, C-P.B.; Gibbons, J.; Xu, J. Discovery of the catechol structural moiety as a Stat3 SH2 domain inhibitor by virtual screening. Bioorg. Med. Chem. Lett., 2008, 18(18), 4988-4992.
[http://dx.doi.org/10.1016/j.bmcl.2008.08.032] [PMID: 18768317]
[25]
Kuck, D.; Singh, N.; Lyko, F.; Medina-Franco, J.L. Novel and selective DNA methyltransferase inhibitors: Docking-based virtual screening and experimental evaluation. Bioorg. Med. Chem., 2010, 18(2), 822-829.
[http://dx.doi.org/10.1016/j.bmc.2009.11.050] [PMID: 20006515]
[26]
Pieper, U.; Webb, B.M.; Dong, G.Q.; Schneidman-Duhovny, D.; Fan, H.; Kim, S.J.; Khuri, N.; Spill, Y.G.; Weinkam, P.; Hammel, M.; Tainer, J.A.; Nilges, M.; Sali, A. ModBase, a database of annotated comparative protein structure models and associated resources. Nucleic Acids Res., 2014, 42(Database issue), D336-D346.
[http://dx.doi.org/10.1093/nar/gkt1144] [PMID: 24271400]
[27]
UniProt Consortium. The Universal Protein Resource (UniProt). Nucleic Acids Res., 2007, 35(Database), D193-D197.
[28]
Benson, D. A.; Karsch-Mizrachi, I.; Lipman, D. J.; Ostell, J.; Sayers, E. W. GenBank. Nucleic Acids Res., 2010, 38(suppl_1), D46-D51.
[29]
Eswar, N.; John, B.; Mirkovic, N.; Fiser, A.; Ilyin, V.A.; Pieper, U.; Stuart, A.C.; Marti-Renom, M.A.; Madhusudhan, M.S.; Yerkovich, B.; Sali, A. Tools for comparative protein structure modeling and analysis. Nucleic Acids Res., 2003, 31(13), 3375-3380.
[http://dx.doi.org/10.1093/nar/gkg543] [PMID: 12824331]
[30]
Shen, M-Y.; Sali, A. Statistical potential for assessment and prediction of protein structures. Protein Sci., 2006, 15(11), 2507-2524.
[http://dx.doi.org/10.1110/ps.062416606] [PMID: 17075131]
[31]
Krebs, B.B.; De Mesquita, J.F. Amyotrophic lateral sclerosis type 20 - in silico analysis and molecular dynamics simulation of hnRNPA1. PLoS One, 2016, 11(7)e0158939
[http://dx.doi.org/10.1371/journal.pone.0158939] [PMID: 27414033]
[32]
Ohno, A.; Jee, J.; Fujiwara, K.; Tenno, T.; Goda, N.; Tochio, H.; Kobayashi, H.; Hiroaki, H.; Shirakawa, M. Structure of the UBA domain of Dsk2p in complex with ubiquitin molecular determinants for ubiquitin recognition. Structure, 2005, 13(4), 521-532.
[http://dx.doi.org/10.1016/j.str.2005.01.011] [PMID: 15837191]
[33]
Huang, X.; Beullens, M.; Zhang, J.; Zhou, Y.; Nicolaescu, E.; Lesage, B.; Hu, Q.; Wu, J.; Bollen, M.; Shi, Y. Structure and function of the two tandem WW domains of the pre-mRNA splicing factor FBP21 (formin-binding protein 21). J. Biol. Chem., 2009, 284(37), 25375-25387.
[http://dx.doi.org/10.1074/jbc.M109.024828] [PMID: 19592703]
[34]
Stout, T.J.; Tondi, D.; Rinaldi, M.; Barlocco, D.; Pecorari, P.; Santi, D.V.; Kuntz, I.D.; Stroud, R.M.; Shoichet, B.K.; Costi, M.P. Structure-based design of inhibitors specific for bacterial thymidylate synthase. Biochemistry, 1999, 38(5), 1607-1617.
[http://dx.doi.org/10.1021/bi9815896] [PMID: 9931028]
[35]
Andersen, J.; Ringsted, K.B.; Bang-Andersen, B.; Strømgaard, K.; Kristensen, A.S. Binding site residues control inhibitor selectivity in the human norepinephrine transporter but not in the human dopamine transporter. Sci. Rep., 2015, 5(1), 15650.
[http://dx.doi.org/10.1038/srep15650] [PMID: 26503701]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 10
ISSUE: 3
Year: 2020
Page: [322 - 332]
Pages: 11
DOI: 10.2174/2210315509666190314145257
Price: $25

Article Metrics

PDF: 19
HTML: 1