Low-dose statin treatment increases prostate cancer aggressiveness

// Alfredo Caro-Maldonado 1 , Laura Camacho 1,2,* , Amaia Zabala-Letona 1,3,* , Verónica Torrano 1,3 , Sonia Fernández-Ruiz 1,3 , Kepa Zamacola-Bascaran 1 , Leire Arreal 1 , Lorea Valcárcel-Jiménez 1 , Natalia Martín-Martín 1,3 , Juana M. Flores 4 , Ana R. Cortazar 1 , Patricia Zúñiga-García 1 , Amaia Arruabarrena-Aristorena 1 , Fabienne Guillaumond 5,6,7,8 , Diana Cabrera 1 , Juan M. Falcón-Perez 1,9,10 , Ana M. Aransay 1,9 , Antonio Gomez-Muñoz 2 , Mireia Olivan 11 , Juan Morote 11 and Arkaitz Carracedo 1,2,3,10 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.