High intratumoral dihydrotestosterone is associated with antiandrogen resistance in VCaP prostate cancer xenografts in castrated mice
Riikka Huhtaniemi,
Petra Sipilä,
Arttu Junnila,
Riikka Oksala,
Matias Knuuttila,
Arfa Mehmood,
Eija Aho,
Teemu D. Laajala,
Tero Aittokallio,
Asta Laiho,
Laura Elo,
Claes Ohlsson,
Malin Hagberg Thulin,
Pekka Kallio,
Sari Mäkelä,
Mika V.J. Mustonen,
Matti Poutanen
Affiliations
Riikka Huhtaniemi
Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, and Turku Center for Disease Modeling, University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland
Petra Sipilä
Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, and Turku Center for Disease Modeling, University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland
Arttu Junnila
Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, and Turku Center for Disease Modeling, University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland
Riikka Oksala
Orion Corporation, Orion Pharma, Turku, Finland
Matias Knuuttila
Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, and Turku Center for Disease Modeling, University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland
Arfa Mehmood
Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
Eija Aho
Orion Corporation, Orion Pharma, Turku, Finland
Teemu D. Laajala
Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, and Turku Center for Disease Modeling, University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland; Department of Mathematics and Statistics, University of Turku, Turku, Finland; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
Tero Aittokallio
Department of Mathematics and Statistics, University of Turku, Turku, Finland; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
Asta Laiho
Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
Laura Elo
Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland; Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, and Turku Center for Disease Modeling, University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland
Claes Ohlsson
Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Region Västra Götaland, Sahlgrenska University Hospital, Department of Drug Treatment, Gothenburg, Sweden
Malin Hagberg Thulin
Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Pekka Kallio
Orion Corporation, Orion Pharma, Turku, Finland
Sari Mäkelä
Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, and Turku Center for Disease Modeling, University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland; Functional Foods Forum, University of Turku, Turku, Finland
Mika V.J. Mustonen
Orion Corporation, Orion Pharma, Turku, Finland
Matti Poutanen
Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, and Turku Center for Disease Modeling, University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland; Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Corresponding author
Summary: Antiandrogen treatment resistance is a major clinical concern in castration-resistant prostate cancer (CRPC) treatment. Using xenografts of VCaP cells we showed that growth of antiandrogen resistant CRPC tumors were characterized by a higher intratumor dihydrotestosterone (DHT) concentration than that of treatment responsive tumors. Furthermore, the slow tumor growth after adrenalectomy was associated with a low intratumor DHT concentration. Reactivation of androgen signaling in enzalutamide-resistant tumors was further shown by the expression of several androgen-dependent genes. The data indicate that intratumor DHT concentration and expression of several androgen-dependent genes in CRPC lesions is an indication of enzalutamide treatment resistance and an indication of the need for further androgen blockade. The presence of an androgen synthesis, independent of CYP17A1 activity, has been shown to exist in prostate cancer cells, and thus, novel androgen synthesis inhibitors are needed for the treatment of enzalutamide-resistant CRPC tumors that do not respond to abiraterone.
