Lipid degradation promotes prostate cancer cell survival
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Harri M. Itkonen1,*, Michael Brown2, Alfonso Urbanucci1,14, Gregory Tredwell3, Chung Ho Lau3, Stefan Barfeld1, Claire Hart2, Ingrid J. Guldvik1, Mandeep Takhar4, Hannelore V. Heemers7,8,9, Nicholas Erho4, Katarzyna Bloch5, Elai Davicioni4, Rita Derua6, Etienne Waelkens6, James L. Mohler10, Noel Clarke2,11,12, Johan V. Swinnen5, Hector C. Keun3, Ole P. Rekvig13, Ian G. Mills1,14,15,*
1Prostate Cancer Research Group, Centre for Molecular Medicine Norway, University of Oslo, Oslo, Norway
2Genito Urinary Cancer Research Group, Institute of Cancer Sciences, University of Manchester, Manchester, United Kingdom
3Department of Surgery and Cancer, Imperial College London, London, United Kingdom
4GenomeDx Biosciences, Vancouver, British Columbia, Canada
5Department of Oncology, Laboratory of Lipid Metabolism and Cancer, LKI Leuven Cancer Institute, KU Leuven-University of Leuven, Leuven, Belgium
6Department of Cellular and Molecular Medicine, Laboratory of Protein Phosphorylation and Proteomics, KU Leuven-University of Leuven, Leuven, Belgium
7Department of Cancer Biology, Cleveland Clinic, Cleveland, Ohio, USA
8Department of Urology, Cleveland Clinic, Cleveland, Ohio, USA
9Department of Hematology/Medical Oncology, Cleveland Clinic, Cleveland, Ohio, USA
10Department of Urology, Roswell Park Cancer Institute, Buffalo, New York, USA
11PCUK/Movember Centre of Excellence for Prostate Cancer Research, CRUK Manchester Institute for Cancer Research, University of Manchester, Manchester, UK
12Department of Urology, The Christie NHS Foundation Trust, Manchester, UK
13Department of Medical Biology, University of Tromso, Tromso, Norway
14Department of Molecular Oncology, Institute for Cancer Research and Oslo University Hospital, Oslo, Norway
15PCUK/Movember Centre of Excellence for Prostate Cancer Research, Centre for Cancer Research and Cell Biology (CCRCB), Queen's University Belfast, Belfast, UK
Harri M. Itkonen, email: email@example.com
Ian G. Mills, email: firstname.lastname@example.org
Keywords: androgen receptor, lipid degradation, metabolism, ECI2, cell cycle
Received: November 17, 2016 Accepted: March 01, 2017 Published: March 11, 2017
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.
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