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Lipid degradation promotes prostate cancer cell survival

2017; Impact Journals LLC; Volume: 8; Issue: 24 Linguagem: Inglês

10.18632/oncotarget.16123

1949-2553

Harri M. Itkonen, Michael D. Brown, Alfonso Urbanucci, Gregory D. Tredwell, Chung‐Ho E. Lau, Stefan J. Barfeld, Claire A. Hart, Ingrid Jenny Guldvik, Mandeep Takhar, Hannelore V. Heemers, Nicholas Erho, Katarzyna Bloch, Elai Davicioni, Rita Derua, Etienne Waelkens, James L. Mohler, Noel W. Clarke, Johan Swinnen, Hector C. Keun, Ole Petter Rekvig, Ian G. Mills,

Lipid metabolism and biosynthesis

// Harri M. Itkonen 1, * , Michael Brown 2 , Alfonso Urbanucci 1, 14 , Gregory Tredwell 3 , Chung Ho Lau 3 , Stefan Barfeld 1 , Claire Hart 2 , Ingrid J. Guldvik 1 , Mandeep Takhar 4 , Hannelore V. Heemers 7, 8, 9 , Nicholas Erho 4 , Katarzyna Bloch 5 , Elai Davicioni 4 , Rita Derua 6 , Etienne Waelkens 6 , James L. Mohler 10 , Noel Clarke 2, 11, 12 , Johan V. Swinnen 5 , Hector C. Keun 3 , Ole P. Rekvig 13 , Ian G. Mills 1, 14, 15, * 1 Prostate Cancer Research Group, Centre for Molecular Medicine Norway, University of Oslo, Oslo, Norway 2 Genito Urinary Cancer Research Group, Institute of Cancer Sciences, University of Manchester, Manchester, United Kingdom 3 Department of Surgery and Cancer, Imperial College London, London, United Kingdom 4 GenomeDx Biosciences, Vancouver, British Columbia, Canada 5 Department of Oncology, Laboratory of Lipid Metabolism and Cancer, LKI Leuven Cancer Institute, KU Leuven-University of Leuven, Leuven, Belgium 6 Department of Cellular and Molecular Medicine, Laboratory of Protein Phosphorylation and Proteomics, KU Leuven-University of Leuven, Leuven, Belgium 7 Department of Cancer Biology, Cleveland Clinic, Cleveland, Ohio, USA 8 Department of Urology, Cleveland Clinic, Cleveland, Ohio, USA 9 Department of Hematology/Medical Oncology, Cleveland Clinic, Cleveland, Ohio, USA 10 Department of Urology, Roswell Park Cancer Institute, Buffalo, New York, USA 11 PCUK/Movember Centre of Excellence for Prostate Cancer Research, CRUK Manchester Institute for Cancer Research, University of Manchester, Manchester, UK 12 Department of Urology, The Christie NHS Foundation Trust, Manchester, UK 13 Department of Medical Biology, University of Tromso, Tromso, Norway 14 Department of Molecular Oncology, Institute for Cancer Research and Oslo University Hospital, Oslo, Norway 15 PCUK/Movember Centre of Excellence for Prostate Cancer Research, Centre for Cancer Research and Cell Biology (CCRCB), Queen's University Belfast, Belfast, UK * Co-corresponding authors Correspondence to: Harri M. Itkonen, email: harri.itkonen@ncmm.uio.no Ian G. Mills, email: ian.mills@ncmm.uio.no Keywords: androgen receptor, lipid degradation, metabolism, ECI2, cell cycle Received: November 17, 2016 Accepted: March 01, 2017 Published: March 11, 2017 ABSTRACT Prostate cancer is the most common male cancer and androgen receptor (AR) is the major driver of the disease. Here we show that Enoyl-CoA delta isomerase 2 (ECI2) is a novel AR-target that promotes prostate cancer cell survival. Increased ECI2 expression predicts mortality in prostate cancer patients ( p = 0.0086). ECI2 encodes for an enzyme involved in lipid metabolism, and we use multiple metabolite profiling platforms and RNA-seq to show that inhibition of ECI2 expression leads to decreased glucose utilization, accumulation of fatty acids and down-regulation of cell cycle related genes. In normal cells, decrease in fatty acid degradation is compensated by increased consumption of glucose, and here we demonstrate that prostate cancer cells are not able to respond to decreased fatty acid degradation. Instead, prostate cancer cells activate incomplete autophagy, which is followed by activation of the cell death response. Finally, we identified a clinically approved compound, perhexiline, which inhibits fatty acid degradation, and replicates the major findings for ECI2 knockdown. This work shows that prostate cancer cells require lipid degradation for survival and identifies a small molecule inhibitor with therapeutic potential.