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Pharmacological upregulation of prostate-specific membrane antigen (PSMA) expression in prostate cancer cells


Kranzbühler, Benedikt; Salemi, Souzan; Umbricht, Christoph A; Müller, Cristina; Burger, Irene A; Sulser, Tullio; Eberli, Daniel (2018). Pharmacological upregulation of prostate-specific membrane antigen (PSMA) expression in prostate cancer cells. The Prostate, 78(10):758-765.

Abstract

BACKGROUND Prostate-specific membrane antigen (PSMA)-based imaging and therapy are increasingly used for prostate cancer management. However, limitations are a low PSMA expression in certain patients. Androgen receptor axis inhibition can induce PSMA expression in vitro. We hypothesized that different approved compounds upregulate PSMA expression and tested their effect in vitro. METHODS Androgen receptor (AR) expressing prostate cancer (LNCaP) and epithelial prostate cells (PNT1A) were treated for 7 days with enzalutamide, dutasteride, rapamycin, metformin, lovastatin, and acetylsalicylic acid (ASA). PSMA and AR protein expression was assessed using flow cytometry, immunocytochemistry and immunoblotting. Furthermore, uptake and internalization of Lu-PSMA-617 was performed. RESULTS Enzalutamide and dutasteride led to a significant (both P < 0.05) upregulation of PSMA surface levels in LNCaP cells. In addition, treatment with rapamycin showed a non-significant trend toward PSMA upregulation. No changes were detected after treatment with vehicle, metformin, lovastatin, and ASA. Total PSMA protein expression was significantly enhanced after treatment with enzalutamide and rapamycin (both P < 0.05), whereas dutasteride led to a non-significant upregulation. Uptake of Lu-PSMA-617 was significantly increased after treatment of LNCaP with enzalutamide, dutasteride, and rapamycin (P < 0.05). In addition, internalization was significantly increased by enzalutamide and rapamycin (P < 0.05), and non-significantly increased by dutasteride. CONCLUSION In conclusion, our data provide new insights into the effect of different approved pharmacological compounds that can markedly upregulate PSMA expression and radioligand uptake in vitro. Pharmacologically induced PSMA expression may prove useful to improve prostate cancer detection and to enhance anticancer effects in PSMA-based therapy.

Abstract

BACKGROUND Prostate-specific membrane antigen (PSMA)-based imaging and therapy are increasingly used for prostate cancer management. However, limitations are a low PSMA expression in certain patients. Androgen receptor axis inhibition can induce PSMA expression in vitro. We hypothesized that different approved compounds upregulate PSMA expression and tested their effect in vitro. METHODS Androgen receptor (AR) expressing prostate cancer (LNCaP) and epithelial prostate cells (PNT1A) were treated for 7 days with enzalutamide, dutasteride, rapamycin, metformin, lovastatin, and acetylsalicylic acid (ASA). PSMA and AR protein expression was assessed using flow cytometry, immunocytochemistry and immunoblotting. Furthermore, uptake and internalization of Lu-PSMA-617 was performed. RESULTS Enzalutamide and dutasteride led to a significant (both P < 0.05) upregulation of PSMA surface levels in LNCaP cells. In addition, treatment with rapamycin showed a non-significant trend toward PSMA upregulation. No changes were detected after treatment with vehicle, metformin, lovastatin, and ASA. Total PSMA protein expression was significantly enhanced after treatment with enzalutamide and rapamycin (both P < 0.05), whereas dutasteride led to a non-significant upregulation. Uptake of Lu-PSMA-617 was significantly increased after treatment of LNCaP with enzalutamide, dutasteride, and rapamycin (P < 0.05). In addition, internalization was significantly increased by enzalutamide and rapamycin (P < 0.05), and non-significantly increased by dutasteride. CONCLUSION In conclusion, our data provide new insights into the effect of different approved pharmacological compounds that can markedly upregulate PSMA expression and radioligand uptake in vitro. Pharmacologically induced PSMA expression may prove useful to improve prostate cancer detection and to enhance anticancer effects in PSMA-based therapy.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Urological Clinic
04 Faculty of Medicine > University Hospital Zurich > Clinic for Nuclear Medicine
Dewey Decimal Classification:610 Medicine & health
Uncontrolled Keywords:Urology, Oncology
Language:English
Date:6 April 2018
Deposited On:20 Jun 2018 12:19
Last Modified:19 Aug 2018 15:33
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:0270-4137
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1002/pros.23522
PubMed ID:29633296

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