Measurement of AhR Ligands in the Tissues of Colon Cancer Patients with XRE Luciferase Reporter

Source:
By:Margarita A Bystriakova, Sergei A Koshkin, Elena N Tolkunova

DOI: https://doi.org/10.30564/jor.v1i1.410

Abstract:

The Aryl hydrocarbon receptor (AhR) ligands exhibiting modulating activity represents a new class of anticancer agents that can be directed towards several tumors. We have examined AhR expression in human colon cancer and adjacent non-tumor tissue. AhR expression level was about 2-7 times higher in tumor tissue samples than in the adjacent non-tumor samples (in 82% of all the samples). We were unable to find any increase of ABCG2 expression on the level of the transcription, while the expression of MDR2 was increased in half of the tumors compared to the levels of expression in normal adjacent tissue. We have used FICZ as a potent high affinity ligand of the AhR to calibrate the reporter cell line HEK293T-AhR-luc as a potent high affinity ligand of the AhR. The concentration of xenobiotic response element (XRE) ligands is higher, than in the blood of healthy people in 86% of the patients. The proposed test system will allow the use of the AhR ligand level as an additional diagnostic marker in the treatment of colon cancer.

References:

[1] C.-E. Boström, P. Gerde, A. Hanberg, B. Jernström, C. Johansson, T. Kyrklund, A. Rannug, M. Törnqvist, K. Victorin, R. Westerholm, Cancer risk assessment, indicators, and guidelines for polycyclic aromatic hydrocarbons in the ambient air, Environmental Health Perspectives, 2002, 110: 451-488. [2] J. Ferlay, I. Soerjomataram, R. Dikshit, S. Eser, C. Mathers, M. Rebelo, D.M. Parkin, D. Forman, F. Bray, Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012, International Journal of Cancer, 2015, 136: E359-E386. [3] D.W. Nebert, Aryl hydrocarbon receptor (AHR): “pioneer member” of the basic-helix/loop/helix per-Arnt-sim (bHLH/PAS) family of “sensors” of foreign and endogenous signals, Progress in Lipid Research, 2017, 67: 38-57. [4] R. Evers, M. Kool, L. van Deemter, H. Janssen, J. Calafat, L.C. Oomen, C.C. Paulusma, R.P. Oude Elferink, F. Baas, A.H. Schinkel, P. Borst, Drug export activity of the human canalicular multispecific organic anion transporter in polarized kidney MDCK cells expressing cMOAT (MRP2) cDNA, The Journal of clinical investigation, 1998, 101: 1310-1319. [5] S.K. Srivastava, S.C. Watkins, E. Schuetz, S.V. Singh, Role of glutathione conjugate efflux in cellular protection against benzo[a]pyrene-7,8-diol-9,10-epoxide–induced DNA damage, Molecular Carcinogenesis, 2002, 33: 156-162. [6] Y. Shirasaka, R. Konishi, N. Funami, Y. Kadowaki, Y. Nagai, T. Sakaeda, S. Yamashita, Expression levels of human P-glycoprotein in In Vitro cell lines: correlation between mRNA and protein levels for P-glycoprotein expressed in cells, Biopharmaceutics & Drug Disposition, 2009, 30: 149-152. [7] C. Wu, S. Yu, Q. Tan, P. Guo, H. Liu, Role of AhR in regulating cancer stem cell–like characteristics in choriocarcinoma, Cell Cycle, 2018, 17: 2309-2320. [8] N.B. Marshall, N.I. Kerkvliet, Dioxin and immune regulation, Annals of the New York Academy of Sciences, 2010, 1183: 25-37. [9] F.J. Quintana, D.H. Sherr, Aryl Hydrocarbon Receptor Control of Adaptive Immunity, Pharmacological Reviews, 2013, 65: 1148-1161. [10] B. Stockinger, P.D. Meglio, M. Gialitakis, J.H. Duarte, The Aryl Hydrocarbon Receptor: Multitasking in the Immune System, Annual Review of Immunology, 2014, 32: 403-432. [11] W. Bock Karl, Human and rodent aryl hydrocarbon receptor (AHR): from mediator of dioxin toxicity to physiologic AHR functions and therapeutic options, Biological Chemistry, 2017: 455. [12] J.U. Kolluri S.K., Safe, S., Role of the aryl hydrocarbon receptor in carcinogenesis and potential as an anti-cancer drug target, Archives of Toxicology, 2017, 91: 17. [13] G. He, T. Tsutsumi, B. Zhao, D.S. Baston, J. Zhao, S. Heath-Pagliuso, M.S. Denison, Third-Generation Ah Receptor–Responsive Luciferase Reporter Plasmids: Amplification of Dioxin-Responsive Elements Dramatically Increases CALUX Bioassay Sensitivity and Responsiveness, Toxicological Sciences, 2011, 123: 511-522. [14] S. Safe, S.-O. Lee, U.-H. Jin, Role of the Aryl Hydrocarbon Receptor in Carcinogenesis and Potential as a Drug Target, Toxicological Sciences, 2013, 135: 1-16. [15] O. van Tellingen, The importance of drug-transporting P-glycoproteins in toxicology, Toxicology Letters, 2001, 120: 31-41. [16] O. Heinisch, Steel, R. G. D., and J. H. Torrie: Principles and Procedures of Statistics. (With special Reference to the Biological Sciences.) McGraw-Hill Book Company, New York, Toronto, London 1960, 481 S., 15 Abb.; 81 s 6 d, Biometrische Zeitschrift, 1962, 4: 207-208. [17] X. Che, W. Dai, Aryl Hydrocarbon Receptor: Its Regulation and Roles in Transformation and Tumorigenesis, Current Drug Targets, 2019, 20: 1-10. [18] I.A. Murray, A.D. Patterson, G.H. Perdew, Aryl hydrocarbon receptor ligands in cancer: friend and foe, Nature Reviews Cancer, 2014, 14: 801. [19] S. Safe, C. Qin, A. McDougal, Development of selective aryl hydrocarbon receptor modulators for treatment of breast cancer, Expert Opinion on Investigational Drugs, 1999, 8: 1385-1396. [20] A. Koliopanos, J. Kleeff, Y. Xiao, S. Safe, A. Zimmermann, M.W. Büchler, H. Friess, Increased arylhydrocarbon receptor expression offers a potential therapeutic target for pancreatic cancer, Oncogene, 2002, 21: 6059.