Enzymatic regulation of the amount and type of ligands for nuclear receptor action

Organization:

Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, University of Turku, Kiinamyllynkatu 10, FI-20520 TURKU, Finland

Institute of Medicine, The Sahlgrenska Academy, Gothenburg University, Vita Stråket 11, Sahlgrenska University Hospital, 41345 Gothenburg, Sweden

Research group:

Petra Sipilä. , PhD, Adjunct Professor; Niina Saarinen-Aaltonen, PhD, Adjunct Professor; Pirjo Pakarinen, PhD, Adjunct Professor; Leena Strauss, PhD, Adjunct Professor; Taija Heinosalo, PhD; Kalle Rytkönen, PhD; Michael Gabriel, MD; Hanna Heikelä, MSc; Arfa Mehmood, MSc; Riikka Huhtaniemi, MSc; Arttu Junnila, MSc

The goal of the projects:

In a traditional view, the endocrine action of steroid hormones is based on the concept where the hormone is synthesized in the gland and reaches the target organ via blood circulation. Our group has been actively involved in studies providing evidence for the concept of “intracrinology”. In the intracrine steroid hormone action, the ligand concentration available for nuclear receptor binding is regulated also by the target tissue metabolism. The work has especially focused on resolving the metabolic pathways in which the HSD17B enzymes play a physiological and/or pathophysiological role. These enzymes catalyze the reaction between the low active 17-keto steroids and the highly active 17-hydroxy steroids, while some of the enzymes have shown to possess essential role also in other metabolic pathways. In our opinion, the key question can be addressed only superficially by in vitro methods, and thus, the specific roles of HSD17B enzymes are addressed by applying GM mouse models, tumor xenografts and by using clinical samples.

We focus on three clinically important hormone-dependent diseases: breast cancer, prostate cancer and endometriosis. All these diseased tissues express a variety of HSD17B enzymes, are highly sex hormone-dependent, and are, thus, potential targets for HSD17B inhibitors.

The specific aimes are:

  1. To define the role of HSD17B enzymes in regulating the amount and type of ligand for nuclear receptor action
  2. To define the role of local sex steroid synthesis in the etiopathogenesis of breast and prostate cancer
  3. To define the role of intra tissue sex steroid synthesis and steroid hormone action in endometrium and the role of the enzymes in etiopathogenesis of endometriosis.

Representative publications:

 

Knuuttila M., Mehmood A., Huhtaniemi R., Häkkinen M., Oksala R., Laajala T.D., Rydberg H., Handelsman D., Aittokallio T., Auriola S., Ohlsson C., Laiho A., Elo L.L., Sipilä P., Mäkelä S., Poutanen M., Antiandrogens reduce intratumoral androgen concentrations and induce androgen receptor expression in castration-resistant prostate cancer xenografts. Am. J. Pathol. 2018 188:216-28.

Järvensivu P., Heinosalo T., Hakkarainen J., Kronqvist P., Saarinen N., Poutanen M., HSD17B1 expression induces inflammation-aided rupture of mammary gland myoepithelium. Endocr. Relat. Cancer, 2018 25:393-406.

Adam M., Heikelä H., Portius D., Sobolewski C., Mäki-Jouppila J., Mehmood A., Adhikari P., Esposito I., Elo L.L., Zhang F.-P., Ruohonen S.T., Strauss L., Foti M., Poutanen M., Hydroxysteroid (17beta) dehydrogenase 13 deficiency triggers hepatic steatosis and inflammation in mice. FASEB J., 2018 32:3434-3447.

Hakkarainen J., Zhang F.-P., Jokela H., Mayerhofer A., Cisneros Montalvo S., Nurmio M, Toppari J., Ohlsson C., Kotaja N., Sipilä P., Poutanen M., Sertoli cell expressed hydroxysteroid (17β) dehydrogenase 1 contributes for steroid synthesis and is required for male fertility. FASEB J., 2018 32:3229-3241.

Heinosalo T., Gabriel M., Kallio L., Adhikari P., Huhtinen K., Laajala D., Kaikkonen E., Mehmood A., Suvitie P., Kujari H., Aittokallio T., Perheentupa A., Poutanen M., Human Secreted Frizzled-Related Protein 2, SFRP2, marks endometriosis lesion borders and acts as a canonical WNT signaling agonist promoting proliferation of endometriosis lesions. Human Reprod., 2018 33:817-831.

Knuuttila M., Mehmood A., Mäki-Jouppila J., Ryberg H., Taimen P., Knaapila J., Ettala O., Boström P.J., Ohlsson C., Venäläinen M.S., Laiho A., Elo L.L., Sipilä P., Mäkelä S.I., Poutanen M., Intratumoral androgen levels are linked to TMPRSS2-ERG fusions in primary prostate cancer. Endocr. Relat. Cancer, 2018 Sep;25(9):807-819.

Huhtaniemi R, Oksala R, Knuuttila M, Mehmood A, Aho E, Laajala TD, Nicorici D, Aittokallio T, Laiho A, Elo L, Ohlsson C, Kallio P, Mäkelä S, Mustonen MVJ, Sipilä P, Poutanen M. Adrenals Contribute to Growth of Castration-Resistant VCaP Prostate Cancer Xenografts. Am J Pathol. 2018 Sep 28. pii: S0002-9440(18)30499-1. doi: 10.1016/j.ajpath.2018.07.029.

 

 

 

Principal Investigator
Matti Poutanen, PhD
Professor of Physiology
Director; Turku Center for Disease Modeling

E-mail: matti.poutanen@utu.fi
Fax: +358-2-2502610
Mobile:+358-50-3660140

Matti Poutanen
Genetically modified mice
Steroid hormone analytics
Drug interventions and
testing in vivo