Activation of interferon-α signaling by resveratrol, genistein and quercetin

Resveratrol, genistein and quercetin from the group of polyphenols from secondary plant metabolites reveal cancer preventive and antivirus effects realized via their pleiotropic influence on the different macromolecules in cells. These compounds can interact with DNA without the formation of covalent bonds. This process is usually followed by changes in spatial, physical-chemical and structural DNA characteristics that can result in disfunction of DNA metabolism enzymes and chromatin destabilization. Similar effects were described for anticancer drug Curaxine CBL0137 in association with activation of interferon-α signaling. We demonstrated dose-dependent stimulating effects of resveratrol, genistein and quercetin on interferon-α signaling using HeLa cells expressed mCherry protein with interferon-stimulated response elements (ISRE) in promoter. Furthermore, it was shown by live-cell fluorescent microscopy in HT1080 cells with mCherry-labeled histone H1.5 that described polyphenols induced the redistribution of this linker histone in cell nuclei. The data obtained suggest an existence of DNA-dependent mechanism of anticancer effects of plant polyphenols and a need for further study of crosslinks between the polyphenols’ influence on chromatin structure and the changes in genome function, in particular, induction of interferon- interferon-α signaling.

plant polyphenols, resveratrol, genistein, quercetin, interferon-α, histone Н1, macromolecules, fluorescence microscopy, metabolism enzymes

1. Pezzuto J.M. Resveratrol: Twenty Years of Growth, Development and Controversy. Biomol Ther (Seoul). 2018 Oct 11. doi: 10.4062/ biomolther.2018.176.

2. Russo M., Russo G.L., Daglia M., Kasi P.D., Ravi S., Nabavi S.F., Nabavi S.M. Understanding genistein in cancer: The «good» and the «bad» effects: A review. Food Chem. 2016 Apr 1; 196: 589–600. doi: 10.1016/j. foodchem.2015.09.085.

3. Rauf A., Imran M., Khan I.A., Ur-Rehman M., Gilani S.A., Mehmood Z., Mubarak M.S. Anticancer potential of quercetin: A comprehensive review. Phytother Res. 2018 Nov; 32 (11): 2109–2130. doi: 10.1002/ ptr.6155.

4. Bishayee A. Cancer prevention and treatment with resveratrol: from rodent studies to clinical trials. Cancer Prev Res (Phila). 2009 May; 2 (5): 409–18. doi: 10.1158/1940‐6207.CAPR‐08‐0160.

5. Whitsett T.G.Jr., Lamartiniere C.A. Genistein and resvera‐ trol: mammary cancer chemoprevention and mechanisms of action in the rat. Expert Rev Anticancer Ther. 2006; 6 (12): 1699–706. doi: 10.1586/14737140.6.12.1699.

6. Barnes S. Effect of genistein on in vitro and in vivo models of cancer. J Nutr. 1995 Mar; 125 (3 Suppl): 777S783S. doi: 10.1093/ jn/125.3_Suppl.777S.

7. Kiskova T., Ekmekcioglu C., Garajova M., Orendas P., Bojkova B., Bobrov N., Jager W., Kassayova M., Thalhammer T. A combination of resveratrol and melatonin exerts chemopreventive effects in N‐methyl‐N‐ nitrosourea‐induced rat mammary carcinogenesis. Eur J Cancer Prev. 2012 Mar; 21 (2): 163–70. doi: 10.1097/CEJ.0b013e32834c9c0f.

8. Fantini M., Benvenuto M., Masuelli L., Frajese G.V., Tresoldi I., Modesti A., Bei R. In vitro and in vivo antitumoral effects of combina‐ tions of polyphenols, or polyphenols and anticancer drugs: perspectives on cancer treatment. Int J Mol Sci. 2015 Apr 24; 16 (5): 9236–82. doi: 10.3390/ijms16059236.

9. Jantan I., Ahmad W., Bukhari S.N. Plant‐derived immunomodula‐ tors: an insight on their preclinical evaluation and clinical trials. Front Plant Sci. 2015 Aug 25; 6: 655. doi: 10.3389/fpls.2015.00655.

10. Britton R.G., Kovoor C., Brown K. Direct molecular targets of res‐ veratrol: identifying key interactions to unlock complex mechanisms. Ann NY Acad Sci. 2015 Aug; 1348 (1): 124–33. doi: 10.1111/nyas.12796.

11. Nagaraju G.P., Zafar S.F., El-Rayes B.F. Pleiotropic effects of genistein in metabolic, inflammatory, and malignant diseases. Nutr Rev. 2013 Aug; 71 (8): 562–72. doi: 10.1111/nure.12044.

12. Chirumbolo S. Quercetin in cancer prevention and therapy. Integr Can‐ cer Ther. 2013 Mar; 12 (2): 97–102. doi: 10.1177/1534735412448215.

13. Kanakis C.D., Tarantilis P.A., Polissiou M.G., Diamantoglou S., Tajmir-Riahi H.A. DNA interaction with naturally occurring antioxidant flavonoids quercetin, kaempferol, and delphinidin. J Biomol Struct Dyn. 2005; 22 (6): 719–24. doi: 10.1080/07391102.2005.10507038.

14. Zhang S., Sun X., Jing Z., Qu F. Spectroscopic analysis on the resveratrol‐DNA binding interactions at physiological pH. Spectrochim Acta A Mol Biomol Spectrosc. 2011 Nov; 82 (1): 213–6. doi: 10.1016/j. saa.2011.07.037.

15. Li H., Yu Y.Y., Hu X.,Cao S.W. Research on the interactions between genistein and its glucosides with DNA. Guang Pu Xue Yu Guang Pu Fen Xi. 2008 Aug; 28 (8): 1905–9.

16. Lipfert J., Klijnhout S., Dekker N.H. Torsional sensing of small‐ molecule binding using magnetic tweezers. Nucleic Acids Res. 2010 Nov; 38 (20): 7122–32. doi: 10.1093/nar/gkq598.

17. Leonova K., Safina A., Nesher E., Sandlesh P., Pratt R., Burkhart C., Lipchick B., Gitlin I., Frangou C., Koman I., Wang J., Kirsanov K., Yakubovskaya M.G., Gudkov A.V., Gurova K. TRAIN (Transcription of Repeats Activates INterferon) in response to chromatin destabilization induced by small molecules in mammalian cells. Elife. 2018 Feb 5; 7. pii: e30842. doi: 10.7554/eLife.30842.

18. Safina A., Cheney P., Pal M., Brodsky L., Ivanov A., Kirsanov K., Lesovaya E., Naberezhnov D., Nesher E., Koman I., Wang D., Wang J., Yakubovskaya M., Winkler D., Gurova K. FACT is a sensor of DNA tor‐ sional stress in eukaryotic cells. Nucleic Acids Res. 2017 Feb 28; 45 (4): 1925–45. doi: 10.1093/nar/gkw1366.

19. Kirsanov K.I., Kotova E., Makhov P., Golovine K., Lesovaya E.A., Kolenko V.M., Yakubovskaya M.G., Tulin A.V. Minor grove binding ligands disrupt PARP‐1 activation pathways. Oncotarget. 2014; 5 (2): 428–37. doi: 10.18632/oncotarget.1742.

20. Izquierdo-Bouldstridge A., Bustillos A., Bonet-Costa C., AribauMiralbes P., Garcia-Gomis D., Dabad M., Esteve-Codina A., PascualReguant L., Peiro S., Esteller M., Murtha M., Millan-Arino L., Jordan A. Histone H1 depletion triggers an interferon response in cancer cells via activation of heterochromatic repeats. Nucleic Acids Res. 2017; 45 (20): 11622–42. doi: 10.1093/nar/gkx746.

21. Yang Z., Meng Q., Zhao Y., Han R., Huang S., Li M., Wu X., Cai W., Wang H. Resveratrol Promoted Interferon‐alpha‐Induced Growth Inhibi‐ tion and Apoptosis of SMMC7721 Cells by Activating the SIRT/STAT1. J Interferon Cytokine Res. 2018 Jun; 38 (6): 261–271. doi: 10.1089/ jir.2017.0130.

22. Igbe I., Shen X.F., Jiao W., Qiang Z., Deng T., Li S., Liu W.L., Liu H.W., Zhang G.L., Wang F. Dietary quercetin potentiates the anti‐ proliferative effect of interferon‐alpha in hepatocellular carcinoma cells through activation of JAK/STAT pathway signaling by inhibition of SHP2 phosphatase. Oncotarget. 2017 Nov 20; 8 (69): 113734–748. doi: 10.18632/ oncotarget.22556.

23. Zhao L.J., He S.F., Liu Y., Zhao P., Bian ZQ., Qi Z.T. Inhibition of STAT Pathway Impairs Anti‐Hepatitis C Virus Effect of Interferon Alpha. Cell Physiol Biochem. 2016; 40 (1–2): 77–90. doi: 10.1159/000452526.