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

doi:10.1016/j.isci.2022.104287

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^*

^*Corresponding author for this work

Turku Bioscience Centre

Research output: Contribution to journal › Article › Scientific › peer-review

6 Citations (Scopus)

59 Downloads (Pure)

Abstract

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.

Original language	English
Article number	104287
Journal	iScience
Volume	25
Issue number	5
DOIs	https://doi.org/10.1016/j.isci.2022.104287
Publication status	Published - 20 May 2022
MoE publication type	A1 Journal article-refereed

Funding

Contributions from nonauthors:, Kim Petterson (University of Turku, Finland) kindly provided reagents for the PSA assay. The authors would like to thank the personnel of Turku Center for Disease Modeling (www.TCDM.fi) and the Histology Core Facility at the Institute of Biomedicine, University of Turku. The Turku Center for Disease Modeling is part of the Biocenter Finland Model Organisms Infrastructure. Funding sources:, The Academy of Finland, Cancer Society of Finland, Drug Research Doctoral Programme, Finnish Cultural Foundation, Orion Pharma, Sigrid Jusélius Foundation, Swedish government, under the Agreement for Medical Education and Research, and the Swedish Research Council and University of Turku. Conceptualization, R.H. P.S. R.O. E.A. M.H.T. P.K. S.M. M.V.J.M. and M.P.; Methodology, R.H. M.K. P.K. S.M. and M.P.; Software, T.D.L. and T.A.; Validation, R.H. and M.P.; Formal Analysis, R.H. A.M. T.D.L. and T.A.; Investigation, R.H.; Resources, P.S. R.O. E.A. T.A. and M.P.; Data Curation, R.H. and M.P.; Writing – Original Draft, R.H. P.S. and M.P.; Writing – Review & Editing, R.H. P.S. R.O. M.K. A.M. E.A. T.D.L. T.A. M.H.T. P.K. S.M. M.V.J.M. and M.P.; Visualization, R.H. and A.M.; Supervision, P.K. S.M. and M.P.; Project Administration, R.H. and M.P.; Funding Acquisition, R.H. E.A. and M.P. R.O. and E.A. are employees and M.V.J.M. and P.K. are former employees of Orion Corporation, Orion Pharma. M.P. is a consultant of Forendo Pharma. The other authors declare no competing interests. The Academy of Finland , Cancer Society of Finland , Drug Research Doctoral Programme , Finnish Cultural Foundation , Orion Pharma , Sigrid Jusélius Foundation , Swedish government , under the Agreement for Medical Education and Research , and the Swedish Research Council and University of Turku .

Keywords

Cancer
Endocrinology

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10.1016/j.isci.2022.104287

High intratumoral dihydrotestosterone is associated with antiandrogen resistance in VCaP prostate cancer xenografts in castrated miceFinal published version, 2.96 MBLicence: CC BY-NC-ND

https://urn.fi/URN:NBN:fi-fe2023022228208

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Huhtaniemi, R., Sipilä, P., Junnila, A., Oksala, R., Knuuttila, M., Mehmood, A., Aho, E., Laajala, T. D., Aittokallio, T., Laiho, A., Elo, L., Ohlsson, C., Thulin, M. H., Kallio, P., Mäkelä, S., Mustonen, M. V. J., & Poutanen, M. (2022). High intratumoral dihydrotestosterone is associated with antiandrogen resistance in VCaP prostate cancer xenografts in castrated mice. iScience, 25(5), Article 104287. https://doi.org/10.1016/j.isci.2022.104287

@article{329922a8ea8b4ddc9f561a2a91952e3f,

title = "High intratumoral dihydrotestosterone is associated with antiandrogen resistance in VCaP prostate cancer xenografts in castrated mice",

abstract = "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.",

keywords = "Cancer, Endocrinology",

author = "Riikka Huhtaniemi and Petra Sipil{\"a} and Arttu Junnila and Riikka Oksala and Matias Knuuttila and Arfa Mehmood and Eija Aho and Laajala, \{Teemu D.\} and Tero Aittokallio and Asta Laiho and Laura Elo and Claes Ohlsson and Thulin, \{Malin Hagberg\} and Pekka Kallio and Sari M{\"a}kel{\"a} and Mustonen, \{Mika V.J.\} and Matti Poutanen",

note = "Funding Information: Contributions from nonauthors:, Kim Petterson (University of Turku, Finland) kindly provided reagents for the PSA assay. The authors would like to thank the personnel of Turku Center for Disease Modeling (www.TCDM.fi) and the Histology Core Facility at the Institute of Biomedicine, University of Turku. The Turku Center for Disease Modeling is part of the Biocenter Finland Model Organisms Infrastructure. Funding sources:, The Academy of Finland, Cancer Society of Finland, Drug Research Doctoral Programme, Finnish Cultural Foundation, Orion Pharma, Sigrid Jus{\'e}lius Foundation, Swedish government, under the Agreement for Medical Education and Research, and the Swedish Research Council and University of Turku. Conceptualization, R.H. P.S. R.O. E.A. M.H.T. P.K. S.M. M.V.J.M. and M.P.; Methodology, R.H. M.K. P.K. S.M. and M.P.; Software, T.D.L. and T.A.; Validation, R.H. and M.P.; Formal Analysis, R.H. A.M. T.D.L. and T.A.; Investigation, R.H.; Resources, P.S. R.O. E.A. T.A. and M.P.; Data Curation, R.H. and M.P.; Writing – Original Draft, R.H. P.S. and M.P.; Writing – Review \& Editing, R.H. P.S. R.O. M.K. A.M. E.A. T.D.L. T.A. M.H.T. P.K. S.M. M.V.J.M. and M.P.; Visualization, R.H. and A.M.; Supervision, P.K. S.M. and M.P.; Project Administration, R.H. and M.P.; Funding Acquisition, R.H. E.A. and M.P. R.O. and E.A. are employees and M.V.J.M. and P.K. are former employees of Orion Corporation, Orion Pharma. M.P. is a consultant of Forendo Pharma. The other authors declare no competing interests. Funding Information: The Academy of Finland , Cancer Society of Finland , Drug Research Doctoral Programme , Finnish Cultural Foundation , Orion Pharma , Sigrid Jus{\'e}lius Foundation , Swedish government , under the Agreement for Medical Education and Research , and the Swedish Research Council and University of Turku . Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2022",

month = may,

day = "20",

doi = "10.1016/j.isci.2022.104287",

language = "English",

volume = "25",

journal = "iScience",

issn = "2589-0042",

publisher = "Cell Press",

number = "5",

}

Huhtaniemi, R, Sipilä, P, Junnila, A, Oksala, R, Knuuttila, M, Mehmood, A, Aho, E, Laajala, TD, Aittokallio, T, Laiho, A, Elo, L, Ohlsson, C, Thulin, MH, Kallio, P, Mäkelä, S, Mustonen, MVJ & Poutanen, M 2022, 'High intratumoral dihydrotestosterone is associated with antiandrogen resistance in VCaP prostate cancer xenografts in castrated mice', iScience, vol. 25, no. 5, 104287. https://doi.org/10.1016/j.isci.2022.104287

TY - JOUR

T1 - High intratumoral dihydrotestosterone is associated with antiandrogen resistance in VCaP prostate cancer xenografts in castrated mice

AU - Huhtaniemi, Riikka

AU - Sipilä, Petra

AU - Junnila, Arttu

AU - Oksala, Riikka

AU - Knuuttila, Matias

AU - Mehmood, Arfa

AU - Aho, Eija

AU - Laajala, Teemu D.

AU - Aittokallio, Tero

AU - Laiho, Asta

AU - Elo, Laura

AU - Ohlsson, Claes

AU - Thulin, Malin Hagberg

AU - Kallio, Pekka

AU - Mäkelä, Sari

AU - Mustonen, Mika V.J.

AU - Poutanen, Matti

N1 - Funding Information: Contributions from nonauthors:, Kim Petterson (University of Turku, Finland) kindly provided reagents for the PSA assay. The authors would like to thank the personnel of Turku Center for Disease Modeling (www.TCDM.fi) and the Histology Core Facility at the Institute of Biomedicine, University of Turku. The Turku Center for Disease Modeling is part of the Biocenter Finland Model Organisms Infrastructure. Funding sources:, The Academy of Finland, Cancer Society of Finland, Drug Research Doctoral Programme, Finnish Cultural Foundation, Orion Pharma, Sigrid Jusélius Foundation, Swedish government, under the Agreement for Medical Education and Research, and the Swedish Research Council and University of Turku. Conceptualization, R.H. P.S. R.O. E.A. M.H.T. P.K. S.M. M.V.J.M. and M.P.; Methodology, R.H. M.K. P.K. S.M. and M.P.; Software, T.D.L. and T.A.; Validation, R.H. and M.P.; Formal Analysis, R.H. A.M. T.D.L. and T.A.; Investigation, R.H.; Resources, P.S. R.O. E.A. T.A. and M.P.; Data Curation, R.H. and M.P.; Writing – Original Draft, R.H. P.S. and M.P.; Writing – Review & Editing, R.H. P.S. R.O. M.K. A.M. E.A. T.D.L. T.A. M.H.T. P.K. S.M. M.V.J.M. and M.P.; Visualization, R.H. and A.M.; Supervision, P.K. S.M. and M.P.; Project Administration, R.H. and M.P.; Funding Acquisition, R.H. E.A. and M.P. R.O. and E.A. are employees and M.V.J.M. and P.K. are former employees of Orion Corporation, Orion Pharma. M.P. is a consultant of Forendo Pharma. The other authors declare no competing interests. Funding Information: The Academy of Finland , Cancer Society of Finland , Drug Research Doctoral Programme , Finnish Cultural Foundation , Orion Pharma , Sigrid Jusélius Foundation , Swedish government , under the Agreement for Medical Education and Research , and the Swedish Research Council and University of Turku . Publisher Copyright: © 2022 The Authors

PY - 2022/5/20

Y1 - 2022/5/20

N2 - 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.

AB - 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.

KW - Cancer

KW - Endocrinology

UR - https://www.scopus.com/pages/publications/85129764826

U2 - 10.1016/j.isci.2022.104287

DO - 10.1016/j.isci.2022.104287

M3 - Article

AN - SCOPUS:85129764826

SN - 2589-0042

VL - 25

JO - iScience

JF - iScience

IS - 5

M1 - 104287

ER -

High intratumoral dihydrotestosterone is associated with antiandrogen resistance in VCaP prostate cancer xenografts in castrated mice

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