Apocryphal FADS2 activity promotes fatty acid diversification in cancer

Reuben S E Young; Andrew P Bowman; Elizabeth D Williams; Kaylyn D Tousignant; Charles L Bidgood; Venkateswara R Narreddula; Rajesh Gupta; David L Marshall; Berwyck L J Poad; Colleen C Nelson; Shane R Ellis; Ron M A Heeren; Martin C Sadowski; Stephen J Blanksby

doi:10.1016/j.celrep.2021.108738

Apocryphal FADS2 activity promotes fatty acid diversification in cancer

Cell Rep. 2021 Feb 9;34(6):108738. doi: 10.1016/j.celrep.2021.108738.

Authors

Affiliations

¹ School of Chemistry and Physics, Queensland University of Technology, Brisbane, QLD 4000, Australia.
² M4I, The Maastricht MultiModal Molecular Imaging Institute, Division of Imaging Mass Spectrometry, Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, the Netherlands.
³ Australian Prostate Cancer Research Centre-Queensland, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology (QUT), Princess Alexandra Hospital, Translational Research Institute, Brisbane, QLD 4000, Australia.
⁴ Central Analytical Research Facility, Institute for Future Environments, Queensland University of Technology, 2 George St., Brisbane, QLD 4000, Australia.
⁵ School of Chemistry and Physics, Queensland University of Technology, Brisbane, QLD 4000, Australia; Central Analytical Research Facility, Institute for Future Environments, Queensland University of Technology, 2 George St., Brisbane, QLD 4000, Australia.
⁶ M4I, The Maastricht MultiModal Molecular Imaging Institute, Division of Imaging Mass Spectrometry, Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, the Netherlands; Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia.
⁷ Australian Prostate Cancer Research Centre-Queensland, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology (QUT), Princess Alexandra Hospital, Translational Research Institute, Brisbane, QLD 4000, Australia; Institute of Pathology, University of Bern, Murtenstrasse 31, 3008 Bern, Switzerland. Electronic address: martin.sadowski@pathology.unibe.ch.
⁸ School of Chemistry and Physics, Queensland University of Technology, Brisbane, QLD 4000, Australia; Central Analytical Research Facility, Institute for Future Environments, Queensland University of Technology, 2 George St., Brisbane, QLD 4000, Australia. Electronic address: stephen.blanksby@qut.edu.au.

PMID: 33567271
DOI: 10.1016/j.celrep.2021.108738

Abstract

Canonical fatty acid metabolism describes specific enzyme-substrate interactions that result in products with well-defined chain lengths, degree(s), and positions of unsaturation. Deep profiling of lipids across a range of prostate cancer cell lines reveals a variety of fatty acids with unusual site(s) of unsaturation that are not described by canonical pathways. The structure and abundance of these unusual lipids correlate with changes in desaturase expression and are strong indicators of cellular phenotype. Gene silencing and stable isotope tracing demonstrate that direct Δ6 and Δ8 desaturation of 14:0 (myristic), 16:0 (palmitic), and 18:0 (stearic) acids by FADS2 generate new families of unsaturated fatty acids (including n-8, n-10, and n-12) that have rarely-if ever-been reported in human-derived cells. Isomer-resolved lipidomics reveals the selective incorporation of these unusual fatty acids into complex structural lipids and identifies their presence in cancer tissues, indicating functional roles in membrane structure and signaling.

Keywords: desaturase; elongase; fatty acids; imaging; isomer; lipids; mass spectrometry; metabolism; prostate cancer; unsaturation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Fatty Acid Desaturases / genetics
Fatty Acid Desaturases / metabolism*
Fatty Acids / biosynthesis*
Fatty Acids / genetics
Gene Silencing
Humans
Male
Neoplasm Proteins / genetics
Neoplasm Proteins / metabolism*
PC-3 Cells
Prostatic Neoplasms / enzymology*
Prostatic Neoplasms / genetics
Prostatic Neoplasms / pathology
Signal Transduction*

Substances

Fatty Acids
Neoplasm Proteins
Fatty Acid Desaturases
FADS2 protein, human