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Lipid degradation promotes prostate cancer cell survival

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Title: Lipid degradation promotes prostate cancer cell survival
Authors: Itkonen, HM
Brown, M
Urbanucci, A
Tredwell, G
Lau, CH
Barfeld, S
Hart, C
Guldvik, IJ
Takhar, M
Heemers, HV
Erho, N
Bloch, K
Davicioni, E
Derua, R
Waelkens, E
Mohler, JL
Clarke, N
Swinnen, JV
Keun, HC
Rekvig, OP
Mills, IG
Item Type: Journal Article
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.
Issue Date: 11-Mar-2017
Date of Acceptance: 1-Mar-2017
URI: http://hdl.handle.net/10044/1/50851
DOI: https://dx.doi.org/10.18632/oncotarget.16123
ISSN: 1949-2553
Publisher: IMPACT JOURNALS LLC
Start Page: 38264
End Page: 38275
Journal / Book Title: ONCOTARGET
Volume: 8
Issue: 24
Copyright Statement: © 2017 Harri M. Itkonen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0 https://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keywords: Science & Technology
Life Sciences & Biomedicine
Oncology
Cell Biology
androgen receptor
lipid degradation
metabolism
ECI2
cell cycle
FATTY-ACID OXIDATION
LARGE GENE LISTS
PERHEXILINE-MALEATE
ANDROGEN RECEPTOR
LEUKEMIA-CELLS
BREAST-CANCER
TUMOR-GROWTH
METABOLISM
INHIBITION
EXPRESSION
ECI2
androgen receptor
cell cycle
lipid degradation
metabolism
Publication Status: Published
Appears in Collections:Division of Surgery
Division of Cancer
Faculty of Medicine



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