Redox signaling (Anna-Liisa Levonen group)

Nrf2 is a transcription factor mainly involved in combating cellular stress caused by reactive oxygen and nitrogen species. However, Nrf2 is also involved in cancer and cardiometabolic diseases, making it an essential drug target.

The main goal of our group is to elucidate the role of Nrf2 in cancer and cardiometabolic diseases, in order to find new targets for the prevention and treatment of these diseases. We are particularly interested in the metabolic control by NRF2, which may play an essential role not only in cancer cell metabolic reprogramming, but also in endothelial cell biology and inflammatory processes.

Research group description

1387ad7aa5fe5aaa9961b35bbeffee27_researchgroup_file

Role of Nrf2-Keap1 signaling

Redox Signaling

Reactive oxygen and nitrogen species (ROS and RNS) and products from their reactions with cellular macromolecules play a significant role in the development of cancer and cardiometabolic diseases. Cells have developed intricate mechanisms by which they respond to ROS and RNS, thereby balancing their effects in cells and tissues. The protective effects are mediated by transcriptional responses to restore cellular homeostasis. The key mediator of cellular protection against ROS and RNS is transcription factor Nrf2, which regulates the expression of numerous protective genes.

Traditionally, Nrf2 has been considered to be beneficial and to protect against many diseases, which has motivated the development of Nrf2 activating drugs for e.g. alleviating neurodegenerative diseases and cancer chemoprevention. However, the levels of Nrf2 are often elevated in cancer increasing cell survival and causing resistance to chemotherapy. The role of Nrf2 in cardiovascular diseases is also controversial, as Nrf2 has been shown to have protective effects in the vasculature, whereas it may have unfavorable systemic metabolic effects that may counteract its local beneficial effects.

Major research topics

– The dichotomous role of NRF2 in cancer, focusing on lung cancer in particular
– Identification of the role of NRF2 in endothelial cell biology
– Metabolic control by NRF2
– The role of Nrf2 in metabolic syndrome and non-alcoholic fatty liver disease.

Research methods

State-of-the-art biochemical, molecular and cell biological techniques, including Next Generation Sequencing techniques, cloning and vector development, RNA-interference techniques and microRNA techniques, proteomics by MS, mouse models, imaging techniques (MRI, ultrasound), small surgery, Isolation of primary cells and histopathology.

Funding sources

Academy of Finland, Finnish Cancer Foundation, Sigrid Juselius Foundation, European Union, EDCMET

Collaborations

Dr. Bruce A. Freeman, University of Pittsburgh, USA, Dr. Franscisco Schopfer, University of Helsinki. Dr. Masayuki Yamamoto, Tohoku School of Medicine, Sendai, Japan, Dr. Eija Pirinen, University of Helsinki, Dr. Emmy Verschuren, University of Helsinki, Dr. Markku Varjosalo, University of Helsinki, Dr. Ville Hietakangas, University of Helsinki, Dr. Jorma Palvimo, University of Eastern Finland, Dr. Jari Koistinaho, University of Eastern Finland, Dr. Kai Kaarniranta, University of Eastern Finland.

Selected publications

1. Cuadrado, A., Rojo, A.I., Wells, G., Hayes, J.D., Cousin, S.P., Rumsey, W.L., Attucks, O.C., Franklin, S., Levonen, A.-L., Kensler, T.W., Dinkova-Kostova, A.T. Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases. Nat Rev Drug Discov. 2019 Apr;18(4):295-317. doi: 10.1038/s41573-018-0008-x.
2. Pölönen P, Jawahar Deen A, Leinonen HM, Jyrkkänen HK, Kuosmanen S, Mononen M, Jain A, Tuomainen T, Pasonen-Seppänen S, Hartikainen JM, Mannermaa A, Nykter M, Tavi P, Johansen T, Heinäniemi M, Levonen AL. Nrf2 and SQSTM1/p62 jointly contribute to mesenchymal transition and invasion in glioblastoma. Oncogene. 2019 Dec;38(50):7473-7490. doi: 10.1038/s41388-019-0956-6. Epub 2019 Aug 23.
3. Kuosmanen SM, Sihvola V, Kansanen E, Kaikkonen MU, Levonen AL. MicroRNAs mediate the senescence-associated decline of NRF2 in endothelial cells. Redox Biol. 2018 Sep;18:77-83. doi: 10.1016/j.redox.2018.06.007. Epub 2018 Jun 22.
4. Ruotsalainen AK, Lappalainen JP, Heiskanen E, Merentie M, Sihvola V, Näpänkangas J, Lottonen-Raikaslehto L, Kansanen E, Adinolfi S, Kaarniranta K, Ylä-Herttuala S, Jauhiainen M, Pirinen E, Levonen AL. Nuclear factor E2-related factor 2 deficiency impairs atherosclerotic lesion development but promotes features of plaque instability in hypercholesterolaemic mice. Cardiovasc Res. 2019 Jan 1;115(1):243-254. doi: 10.1093/cvr/cvy143.
5. Deen AJ, Sihvola V, Härkönen J, Patinen T, Adinolfi S, Levonen AL. Regulation of stress signaling pathways by nitro-fatty acids. Nitric Oxide. 2018 Mar 19:S1089-8603(17)30323-3. doi: 10.1016/j.niox.2018.03.012. Online ahead of print.
6. Kuosmanen SM, Kansanen E, Kaikkonen MU, Sihvola V, Pulkkinen K, Jyrkkänen HK, Tuoresmäki P, Hartikainen J, Hippeläinen M, Kokki H, Tavi P, Heikkinen S, Levonen AL. NRF2 regulates endothelial glycolysis and proliferation with miR-93 and mediates the effects of oxidized phospholipids on endothelial activation. Nucleic Acids Res. 2018 Feb 16;46(3):1124-1138. doi: 10.1093/nar/gkx1155.
7. Küblbeck J, Vuorio T, Niskanen J, Fortino V, Braeuning A, Abass K, Rautio A, Hakkola J, Honkakoski P, Levonen AL.
The EDCMET Project: Metabolic Effects of Endocrine Disruptors. Int J Mol Sci. 2020 Apr 24;21(8):3021. doi: 10.3390/ijms21083021.
8. Patinen T, Adinolfi S, Cortés CC, Härkönen J, Jawahar Deen A, Levonen AL. Regulation of stress signaling pathways by protein lipoxidation. Redox Biol. 2019 May;23:101114. doi: 10.1016/j.redox.2019.101114. Epub 2019 Jan 16.
9. Ruotsalainen, A.K., Lappalainen, J.P., Heiskanen, E., Merentie, M., Sihvola, V., Näpänkangas, J., Lottonen-Raikaslehto, L., Kansanen, E., Adinolfi, S., Kaarniranta, K., Ylä-Herttuala, S., Jauhiainen, M., Pirinen, E., Levonen, A.-L. Nrf2 deficiency impairs atherosclerotic lesion development but promotes features of plaque instability in hypercholesterolemic mice. Cardiovasc. Res., 115:243-254, 2019.
10. Kuosmanen, S.M., Kansanen, E., Kaikkonen, M.U., Sihvola, V., Pulkkinen, K., Jyrkkänen, H.-K., Tuoresmäki, P., Hartikainen, J., Hippeläinen, M., Kokki, H., Tavi, P., Heikkinen, S., Levonen, A.-L. NRF2 regulates endothelial glycolysis and proliferation with miR-93 and mediates the effects of oxidized phospholipids on endothelial activation. Nucleic Acids Res. 46:1124-1138, 2018.
11. Kuosmanen, S.M., Viitala, S., Laitinen, T., Peräkylä, M., Pölönen, P., Kansanen, E., Leinonen, H., Raju, S., Wienecke-Baldacchino, A. Närvänen, A., Poso, A., Heinäniemi, M., Heikkinen, S., Levonen, A.-L. The Effects of Sequence Variation on Genome-wide NRF2 Binding – New Target Genes and Regulatory SNPs. Nucleic Acids Res. 44:1760-1775, 2016.
12. Leinonen, H.M., Kansanen, E., Pölönen, P., Heinäniemi, M., Levonen, A.-L. Role of the Keap1-Nrf2 Pathway in Cancer. Adv. Cancer Res. 122: 281-320, 2014.
13. Ruotsalainen, A.-K., Inkala, M., Partanen, M.E., Lappalainen, J.P., Kansanen, E., Mäkinen, P.I., Heinonen, S.E., Laitinen, H.M., Heikkilä, J., Vatanen, T., Hörkkö, S., Yamamoto, M., Ylä-Herttuala, S., Jauhiainen, M., Levonen, A.-L. The absence of macrophage Nrf2 promotes early atherogenesis. Cardiovasc. Res. 98:107-115, 2013.
14. Leinonen, H.M., Ruotsalainen, A.-K., Määttä, A.M., Laitinen, H.M., Kuosmanen, S.M., Kansanen, E., Pikkarainen, J.T., Lappalainen, J.P., Samaranayake, H., Lesch, H.P., Kaikkonen, M.U., Ylä-Herttuala, S., Levonen, A.-L. Oxidative stress-regulated lentiviral TK/GCV gene therapy for lung cancer treatment. Cancer Res. 72:6227-6235, 2012.
15. Kansanen, E., Bonacci, G., Schopfer, F.J., Linna, S., Tong, K.I., Leinonen, H., Woodcock, S.R., Yamamoto, M., Carlberg, C., Ylä-Herttuala, S., Freeman, B.A., Levonen, A.-L. Electrophilic nitro-fatty acids activate Nrf2 by a Keap1 cysteine 151-independent mechanism. J. Biol. Chem. 286:14019-14027, 2011.
16. Kansanen, E., Jyrkkänen, H.K., Volger O.L., Leinonen, H., Kivelä, A.M., Häkkinen, S.-K., Woodcock, S.R., Schopfer, F.J., Horrevoets, A.J, Ylä-Herttuala, S., Freeman, B.A., Levonen, A.-L. Nrf2-dependent and independent responses to nitro-fatty acids in human endothelial cells: identification of heat shock response as a major pathway activated by nitro-oleic acid. J. Biol. Chem. 284:33233-33241, 2009.
17. Jyrkkänen, H.-K., Kansanen, E., Inkala, M., Kivelä, A.M., Hurttila, H., Heinonen, S.E., Goldsteins, G., Jauhiainen, S., Tiainen, S., Makkonen, H., Oskolkova, O., Afonyushkin, T., Koistinaho, J., Yamamoto, M., Bochkov, V.N., Ylä-Herttuala, S., Levonen, A.-L. Nrf2 regulates antioxidant gene expression evoked by oxidized phospholipids in endothelial cells and murine arteries in vivo. Circ. Res. 103: e1-9, 2008.

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Keywords

Group members - UEF