Redox Signaling // Science

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.

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.

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

Finnish Cancer Foundation, Sigrid Juselius Foundation, European Union

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. in press
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. 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.