Oncotarget

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Low-dose statin treatment increases prostate cancer aggressiveness

Alfredo Caro-Maldonado, Laura Camacho, Amaia Zabala-Letona, Verónica Torrano, Sonia Fernández-Ruiz, Kepa Zamacola-Bascaran, Leire Arreal, Lorea Valcárcel-Jiménez, Natalia Martín-Martín, Juana M. Flores, Ana R. Cortazar, Patricia Zúñiga-García, Amaia Arruabarrena-Aristorena, Fabienne Guillaumond, Diana Cabrera, Juan M. Falcón-Perez, Ana M. Aransay, Antonio Gomez-Muñoz, Mireia Olivan, Juan Morote and Arkaitz Carracedo _

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Oncotarget. 2018; 9:1494-1504. https://doi.org/10.18632/oncotarget.22217

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Abstract

Alfredo Caro-Maldonado1, Laura Camacho1,2,*, Amaia Zabala-Letona1,3,*, Verónica Torrano1,3, Sonia Fernández-Ruiz1,3, Kepa Zamacola-Bascaran1, Leire Arreal1, Lorea Valcárcel-Jiménez1, Natalia Martín-Martín1,3, Juana M. Flores4, Ana R. Cortazar1, Patricia Zúñiga-García1, Amaia Arruabarrena-Aristorena1, Fabienne Guillaumond5,6,7,8, Diana Cabrera1, Juan M. Falcón-Perez1,9,10, Ana M. Aransay1,9, Antonio Gomez-Muñoz2, Mireia Olivan11, Juan Morote11 and Arkaitz Carracedo1,2,3,10

1 CIC bioGUNE, Bizkaia Technology Park, Derio, Spain

2 Biochemistry and Molecular Biology Department, University of the Basque Country, Bilbao, Spain

3 CIBERONC, Madrid, Spain

4 Department of Animal Medicine and Surgery, School of Veterinary Medicine, Complutense University of Madrid, Madrid, Spain

5 Centre de Recherche en Cancérologie de Marseille, U1068, Institut National de la Santé et de la Recherche Médicale, Paris, France

6 Institut Paoli-Calmettes, Marseille, France

7 UMR 7258, Centre National de la Recherche Scientifique, Paris, France

8 Université Aix-Marseille, Marseille, France

9 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain

10 IKERBASQUE, Basque foundation for science, Bilbao, Spain

11 Department of Urology and Research Group in Urology, Vall d´Hebron Hospital, Vall d´Hebron Research Institute, and Universitat Autònoma de Barcelona, Barcelona, Spain

* These authors have contributed equally to this work

Correspondence to:

Arkaitz Carracedo, email:

Keywords: prostate cancer; statins; cholesterol; obesity; mouse models

Received: July 13, 2017 Accepted: October 13, 2017 Published: October 31, 2017

Abstract

Prostate cancer is diagnosed late in life, when co-morbidities are frequent. Among them, hypertension, hypercholesterolemia, diabetes or metabolic syndrome exhibit an elevated incidence. In turn, prostate cancer patients frequently undergo chronic pharmacological treatments that could alter disease initiation, progression and therapy response. Here we show that treatment with anti-cholesterolemic drugs, statins, at doses achieved in patients, enhance the pro-tumorigenic activity of obesogenic diets. In addition, the use of a mouse model of prostate cancer and human prostate cancer xenografts revealed that in vivo simvastatin administration alone increases prostate cancer aggressiveness. In vitro cell line systems supported the notion that this phenomenon occurs, at least in part, through the direct action on cancer cells of low doses of statins, in range of what is observed in human plasma. In sum, our results reveal a prostate cancer experimental system where statins exhibit an undesirable effect, and warrant further research to address the relevance and implications of this observation in human prostate cancer.


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