Oncotarget

Research Papers:

Lipid degradation promotes prostate cancer cell survival

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

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Oncotarget. 2017; 8:38264-38275. https://doi.org/10.18632/oncotarget.16123

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Abstract

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

*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.


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