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

iScience (May 2022)

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

Journal volume & issue: Vol. 25, no. 5
p. 104287

Abstract

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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.

Published in iScience

ISSN: 2589-0042 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science
Website: http://www.cell.com/iscience/home

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