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 K. Takhar, Hannelore Heemers, Nicholas Erho, Katarzyna Bloch, Elai Davicioni, Rita Derua, Etienne Waelkens, James L Mohler, Noel Clarke, Johan V Swinnen, Hector C Keun, Ole P RekvigIan G Mills

Research output: Contribution to journalArticlepeer-review

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 ARtarget 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.
Original languageEnglish
Pages (from-to)38264-38275
Number of pages11
JournalOncotarget
Volume8
Issue number24
DOIs
Publication statusPublished - 11 Mar 2017

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre

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